Symptoms and General Pathology

All Conditions

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Diseases and Abnormalities at or Before Birth

Gland and Hormone Related Diseases

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Infertility

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Testicular Neoplasms

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Infertility, Male

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Genital Diseases, Male

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Male Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Methyltestosterone

Androgens

Testosterone

Testosterone undecanoate

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Testosterone 17 beta-cypionate

Castor Oil

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Castor

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

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

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.

Andrea Lenzi, MD

Andrea Isidori, MD, PhD

Vincenzo Bonifacio, MD, PhD

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.

Androgen for Leydig Cell Proliferation

Androgen Treatment in Leydig Cell Proliferation

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).

Percentage change in the area of the lesion (measured with computer assisted graphics).

Reduction of the serum Luteinizing Hormone (LH) levels during testosterone therapy

Evaluation of sperm cell production after testosterone withdrawal.

Changes in the number of areas / nodules / lesions in the long-term safety assessment

University of Roma La Sapienza

Professor of Endocrinology

Recurrence

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Prostatic Diseases

Follicle Stimulating Hormone

At the start of the study: 240 mg of the gonadotropin releasing hormone antagonist Degarelix (Ferring GmbH, Wittland, Kiel, Germany) + recombinant FSH (Gonal-f, Merck Serrono S.A. Aubonne, Schweiz), 300 IU every second day for 5 weeks.

After 3 weeks: 1000 mg testosterone once.

At the start of the study: 240 mg of the gonadotropin releasing hormone antagonist Degarelix (Ferring GmbH, Wittland, Kiel, Germany).

After 3 weeks: 1000 mg testosterone (Nebido, Bayer AB, Solna, Sweden) once.

Two doses of degarelix, 240 mg, subcutaneously once, at study start.

Degarelix 120 MG [Firmagon]

Gonal-f 300 IU subcutaneously 3 times per week for 5 weeks.

Gonal F RFF Pen 900 UNT Per 1.5 ML Pen Injector

One dose 1000 mg testosterone once, after 3 weeks.

Testosterone Undecanoate

Yvonne Lundberg Giwercman, Professor

In order to elucidate if FSH can have testosterone like effects, samples from young, non-smoking healthy volunteers, with normal body mass index, and with pharmacologically induced gonadotropin deficiency will be studied regarding their capacity to induce prostate specific antigen (PSA), which normally is regulated by testosterone.

Normally, prostate specific antigen (PSA), which is a marker for prostate disease and progression, is exclusively produced in response to testosterone. In order to elucidate if follicle stimulating hormone (FSH) can have testosterone like effects, samples from n=30 non-smoking healthy volunteers, 20-30 years of age and with normal body mass index (20-25) with pharmacologically induced gonadotropin deficiency will be studied. The men are currently recruited and during 5 weeks undergoing:

1. Pharmacologically induced gonadotropin deficiency w 1-3;
2. FSH-treatment of 50% (group A), w 1-5;
3. Testosterone (T) treatment of all (group A and B) w 4-5;
4. End and follow up after 5 weeks.

A subcutaneous injection with the GnRH antagonist degarelix (240 mg¸ Ferring GmbH Wittland, Kiel, Germany) results in drop of both FSH and LH-induced testosterone. Half of the men will get recombinant FSH (300 IU; Gonal-f, Merck Serrono S.A. Aubonne, Schweiz) back, whereas 50% will not. Three weeks thereafter, the full spectrum of FSH dependent changes occur and are reflected in blood. From this occasion testosterone (Nebido, Ferring GmbH Wittland, Kiel, Germany) will be given to all participants to diminish the side-effects of the castration. Blood samples are collected at start, after 3 wks and after 5 wks. At that point also a follow up is undertaken. This experimental design will provide samples from each individual during normal conditions, during castration, and after a standardised dose of FSH.

Randomized case control study: one arm with FSH treatment for 5 weeks and one arm without FSH.

The Role of Follicle Stimulating Hormone in Advanced Prostate Cancer

Case Control Study Regarding the Role of Follicle Stimulating Hormone in Chemically Castrated Young Men

Swedish Cancer Foundation

ALF Swedish Government Grant

Lund University

Oral Testosterone Therapy-396 mg given twice per day on days 1-7 and 15-21 of a 28 day cycle until radiographic progression. After a 21 day washout period, Enzalutamide therapy given at 160 mg once daily will be taken for a maximum of 6 cycles while on study.

Enzalutamide

Samuel Denmeade, MD

Rana Sullivan, RN

Shifeng Moa

Previous studies of high dose testosterone therapy given intramuscularly to men with metastatic castrate resistant prostate cancer suggest that high serum levels of testosterone may be required for clinical response. This injection regimen was given as one dose of 400mg injection every 28 days, which initially produces high serum testosterone levels but these levels drop to a varying degree in some men over the 28-day cycle.

In this 30 patient trial will analyze the effects of oral testosterone therapy in men with metastatic castrate resistant prostate cancer taken on a schedule of seven days of oral testosterone therapy followed by seven days of no therapy for a twenty-eight day cycle. This therapy will be given for three 28 day cycles consecutively followed by radiographic scans to evaluate the metastatic disease. Patients will be allowed to continue on this therapy until the patients show signs of radiographic progression. If the patients show signs of radiographic progression after the first three cycles, the patients will stop taking the oral testosterone therapy and begin taking enzalutamide therapy. Enzalutamide therapy will be taken for three 28 day cycles, then radiographic scans will be taken. If there are no signs of radiographic progression, patients can continue to take enzalutamide therapy for an additional 3 cycles while on study. Patients with continued PSA or objective response will come off study but continue on enzalutamide as standard of care therapy.

This study will help the investigators to understand if treating these men with the highest FDA approved dose of oral testosterone therapy will achieve similar and sustained high levels of serum testosterone that will produce similar or enhanced therapeutic response to the therapy when compared to the serum testosterone levels found in the previous injection therapy trials.

Metastatic prostate cancer is a highly significant disease that claims the lives of approximately 30,000 American men each year. Androgen Deprivation Therapy (ADT) is initially very effective but is never curative as all men eventually develop castrate resistant prostate cancer (CRPC). A major factor driving resistance is the ability of prostate cancer (PCa) cells to adapt to the chronic low androgen conditions by upregulating androgen receptor (AR) activity through overexpression, gene amplification and expression of truncated, transcriptionally active AR variants that lack the ligand-binding domain. Persistent signaling through AR makes CRPC sensitive to more potent inhibition of AR by abiraterone acetate or second generation anti-androgens such as enzalutamide. Yet these therapies have a limited duration of benefit prior to development of resistance, often through further increase in AR levels.

While this marked upregulation of AR can drive resistance, the investigators have demonstrated that it also creates a therapeutic vulnerability to exposure to high levels of androgen. However, the investigators have also found that sustained exposure of CRPC to supraphysiological levels of androgens results in downregulation of AR and acquired resistance to this therapy. Therefore the investigators have developed a therapy called Bipolar Androgen Therapy (BAT) in which testosteronecypionate 400 mg IM is administered every 28 days to result in cycling from supraphysiological (\>1500 ng/dL) to near-castrate levels. The rationale for cycling was that high serum T would kill high AR expressing CRPC while low serum T would prevent adaptation to high T and kill low AR expressing CRPC.

To date the investigators have treated approximately 250 men with BAT across four completed studies in asymptomatic men with CRPC. The key findings have been that BAT: (a) could be safely administered; (b) did not produce symptomatic disease progression; (c) produced sustained PSA and objective responses in approximately 30-40% of patients; (d) re-sensitized and prolonged response of patients to subsequent antiandrogen therapy. While ADT for advanced PCa often produces debilitating sexual and metabolic side effects, another highly significant feature of this approach is that BAT can make men feel remarkably better by decreasing fatigue, increasing physical activity and restoring libido and sexual function. BAT also produced favorable effects on body composition by increasing skeletal muscle mass and decreasing subcutaneous and visceral fat. Thus, incorporation of BAT into the treatment paradigm has the potential to improve the quality of life and well-being of PCa patients and minimize the morbidity from the metabolic sequelae produced by androgen ablative therapies.

The studies performed to date demonstrate the safety and efficacy of high dose T in men with metastatic CRPC who are progressing on androgen ablative therapy. The investigators' limited data suggests that high serum levels of T may be required for clinical response. This high level has is achieved through intramuscular (IM) administration of testosterone cypionate at the highest FDA-approved dose of 400 mg every 28 days. This regimen initially produces high serum T levels but these levels drop to a varying degrees approaching near castrate levels in some men over a 28-day cycle. To date, the investigators have not tested whether more rapid cycling of serum T would produce similar or improved therapeutic response in this patient population. Additional issues with IM testosterone are (1) it requires patients to come to hospital every 28 days for injection, (2) has highly variable pharmacokinetics, (3) can cause physical discomfort from IM injections.

Recently two novel oral testosterone (OT) agents were developed for the treatment of male hypogonadism. Historically, an oral option for testosterone replacement therapy was unavailable because of risks of liver toxicity, including cholestasis and jaundice, associated with earlier developed 17-alpha-alkylated oral analogs. These novel oral agents feature specialized formulations that avoid adverse hepatic effects. In clinical trials, both oral agents produced no significant adverse effects on liver function tests. The investigators have formed a collaborative partnership with Clarus Therapeutics, the makers of Jatenzo, an oral lipoprotein-coated testosterone undecanoate (OT) formulation that was FDA-approved in December 2019 as T-replacement therapy. Published pharmacokinetic data demonstrate that OT can produce supraphysiologic serum T levels when administered at the highest FDA-approved dose. Therefore, the investigators' hypothesis is that OT, given at the highest FDA approved dose, will achieve more homogeneous and sustained supraphysiologic levels of serum T that will produce similar or enhanced therapeutic response. To avoid adaptation of CRPC to this sustained level of T, the investigators will utilize a dosing schedule of 1 week-on, 1 week-off.

Safety and Efficacy of Oral Testosterone Undecanoate Followed by Enzalutamide as Therapy for Men With Metastatic Castrate Resistant Prostate Cancer

A Phase II Study Assessing the Safety and Efficacy of Oral Testosterone Undecanoate Followed by Enzalutamide as Therapy for Men With Metastatic Castrate Resistant Prostate Cancer

Radiographic responses to Oral Testosterone therapy using CT scan measurements. Radiographic progression is assessed by RECIST (Response Evaluation Criteria in Solid Tumors). Per RECIST, progression is defined as ≥ 20% and ≥ 5 mm from nadir of the sum of the diameters of target lesions.

Number of participants with PSA50 response to Oral Testosterone therapy defined as at least a 50% decline in Prostate Specific Antigen (PSA) from baseline value.

Number of weeks from baseline until PSA progression.

Number of weeks from baseline until radiographic or clinical progression, whichever comes first. Radiographic progression is assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate Cancer Working Group 3 (PCWG3) criteria. Per RECIST, progression is defined as ≥ 20% and ≥ 5 mm from nadir of the sum of the diameters of target lesions. Per PCWG3 criteria, radiographic progression is defined as ≥ 20% sum of the longest diameter of target lesions, or ≥ 2 new lesions on bone scan from baseline. Clinical progression is defined as new spinal cord or nerve root compression, new pathologic fracture or use of opioid analgesics for cancer-related pain.

Number of participants with PSA50 response to enzalutamide therapy defined as at least a 50% decline in Prostate Specific Antigen (PSA) from baseline value.

Radiographic responses to Enzalutamide therapy using CT scan measurements after 3 cycles and after 6 cycles of therapy. Radiographic progression is assessed by RECIST (Response Evaluation Criteria in Solid Tumors) criteria ). Per RECIST, progression is defined as ≥ 20% and ≥ 5 mm from nadir of the sum of the diameters of target lesions.

Mean peak testosterone level (ng/dL) measured at 4 hours post first dose of oral testosterone therapy.

Mean trough testosterone level (ng/dL) measured within 24, 48, 72 or 96 hours after cycle 1 day 7 dose of oral testosterone therapy

Phenotype of peripheral blood mononucleated cell (PBMC) as defined by number of cluster of differentiation 4 (CD4) Tcells, cluster of differentiation 8 (CD8) Tcells, FOXP3+ Treg cells, B cells, Natural Killer (NK) cells, monocytes, dendritic cells, and myeloid derived suppressor cells. PBMCs will be immunophenotyped using multiparameter flow cytometry.

The Functional Assessment of Chronic Illness Therapy - Fatigue has a score range of 0-52 with higher scores indicating better quality of life.

All questions are scored on a scale from 0 to 100. The total score from all of the questions answered is divided by the total number of the questions answered yielding a global score from 0-100 with 100 representing the highest level of functioning possible.

Safety as assessed by adverse event reporting. Grading of adverse events will be done by utilizing the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Determination of relationship of the adverse event to the study procedures or study drug will be performed by the PI using the standard attribution terminology (e.g. unrelated, possibly related, etc.).

Tolerability as assessed by adverse event reporting. Grading of adverse events will be done by utilizing the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Determination of relationship of the adverse event to the study procedures or study drug will be performed by the PI using the standard attribution terminology (e.g. unrelated, possibly related, etc.).

Number of weeks from start of enzalutamide treatment until PSA progression.

Number of weeks from start of oral testosterone therapy until PSA progression while on enzalutamide treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Androgen for Leydig Cell Proliferation	NCT01206270	Klinefelter Syn... Hypergonadotrop... Hypergonadotrop... Hypergonadotrop...	Testosterone un... Castor Oil	18 Years - 60 Years	University of Roma La Sapienza
Androgen for Leydig Cell Proliferation	NCT01206270	Klinefelter Syn... Hypergonadotrop... Hypergonadotrop... Hypergonadotrop...	Testosterone un... Castor Oil	18 Years - 60 Years	University of Roma La Sapienza
The Role of Follicle Stimulating Hormone in Advanced Prostate Cancer	NCT04134130	Prostate Cancer...	Degarelix 120 M... Gonal F RFF Pen... Testosterone Un...	20 Years - 30 Years	Lund University
Safety and Efficacy of Oral Testosterone Undecanoate Followed by Enzalutamide as Therapy for Men With Metastatic Castrate Resistant Prostate Cancer	NCT05081193	Prostate Cancer Castration-resi... Metastatic Cast...	Testosterone Un... Enzalutamide	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
The Role of Follicle Stimulating Hormone in Advanced Prostate Cancer	NCT04134130	Prostate Cancer...	Degarelix 120 M... Gonal F RFF Pen... Testosterone Un...	20 Years - 30 Years	Lund University

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