Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

All Conditions

Symptoms and General Pathology

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diabetes Mellitus

Syndrome

Prostatic Neoplasms

Obesity

Metabolic Syndrome

Metabolic Diseases

Hypogonadism

Eunuchism

Insulin Resistance

Hyperinsulinism

Glucose Metabolism Disorders

Gonadal Disorders

Endocrine System Diseases

All Drugs and Chemicals

Androgens

Testosterone

Hormones

Hormone Antagonists

20 Eugonadal Healthy men 20 Men with Testosterone Deficiency not currently on Testosterone replacement therapy

20 Men with Testosterone Deficiency progressed from OBS1 6 months post initiation of testosterone replacement therapy

20 men with prostate cancer planned for GnRH analogue therapy

In OBS1 20 men will be started on Testosterone replacement therapy as per routine clinical practice. Data collection will occur prior initiating therapy, and 6 months post

20 men in OBS2 planned for GnRH analogue therapy will undergo data collection prior, and 3 months post initiation of GnRH analogue therapy

GnRH

Michael O' Reilly, FRCPI PhD

Clare Miller, MBBS

Michael Professor O'Reilly, FRCPI PhD

Clare Dr Miller, BM BS

This study relates to men with hypogonadism, a condition describing a deficiency of androgens such as testosterone. Deficiency of these hormones occurs in men due to testicular (primary) or hypothalamic-pituitary (secondary) problems or may be observed in men undergoing androgen deprivation therapy for prostate cancer.

Testosterone plays an important role in male sexual development and health, but also plays a key role in metabolism and energy balance. Men with testosterone deficiency have higher rates of metabolic dysfunction. This results in conditions such as obesity, nonalcoholic fatty liver disease, diabetes, and cardiovascular disease. Studies have confirmed that treating testosterone deficiency with testosterone can reduce the risk of some of these adverse metabolic outcomes, however cardiovascular mortality remains higher than the general population. We know that testosterone deficiency therefore causes metabolic dysfunction. However, research to date has not established the precise mechanisms behind this.

In men with hypogonadism there is a loss of skeletal muscle bulk and function. Skeletal muscle is the site of many critical metabolic pathways; therefore it is likely that testosterone deficiency particularly impacts metabolic function at this site. Men with testosterone deficiency also have excess fat tissue, this can result in increased conversion of circulating hormones to a type of hormone which further suppresses production of testosterone. The mechanism of metabolic dysfunction in men with hypogonadism is therefore multifactorial.

The purpose of this study is to dissect the complex mechanisms linking obesity, androgens and metabolic function in men. Firstly, we will carry out a series of detailed metabolic studies in men with testosterone deficiency, compared to healthy age- and BMI-matched men. Secondly, we will perform repeat metabolic assessment of hypogonadal men 6 months after replacement of testosterone in order to understand the impact of androgen replacement on metabolism. Lastly, we will perform the same detailed metabolic assessment in men with prostate cancer before and after introduction of a drug which causes testosterone deficiency for therapeutic purposes.

Male hypogonadism occurs due to a deficiency of androgens such as testosterone due to either primary (testicular) or secondary (hypothalamic pituitary) pathology. The incidence of testosterone deficiency is likely to increase with more cancer survivors, opiate use, increased awareness and thus diagnosis of testosterone deficiency. Hypogonadism in males is an independent risk factor for the development of metabolic syndrome and is associated with increased prevalence of insulin resistance, type two diabetes, non-alcoholic fatty liver disease, visceral adiposity, and cardiovascular disease.

The relationship between hypogonadism and metabolic dysfunction is bidirectional with secondary hypogonadism documented in a large proportion of men with obesity without a testicular or central cause of androgen deficiency. A vicious cycle exists whereby increased adipose tissue in men with obesity results in depleting circulating testosterone stores due to increased aromatisation of testosterone to oestrogen and suppression of gonadotrophin mediated testosterone secretion via negative feedback. This perpetuates visceral adiposity in men with pre-existing metabolic dysfunction.

The hormonal impact of visceral adiposity plays a role in aggravating metabolic disease in men with hypogonadism however the initial metabolic perturbation causing obesity and metabolic disease in these men has not been established. It is probable skeletal muscle dysfunction is a major player. Skeletal muscle is the primary site for glucose uptake and utilisation and houses critical metabolic pathways such as oxidative phosphorylation in mitochondria. Men with hypogonadism experience loss of skeletal muscle bulk and function. Research has previously demonstrated that pathologic alterations in androgen exposure result in mitochondrial dysfunction in females. Studies have also confirmed improvements in mitochondrial function include increased phosphorylation of AMPKα in men with diabetes and hypogonadotropic hypogonadism and in animal models increased expression of genes related to mitochondrial respiration enzymes following introduction of testosterone(12). These findings hint at a pivotal role for androgens in mitochondrial function and energy biogenesis in skeletal muscle. However, to date no mechanistic study has established the precise cellular mechanisms adversely modified by androgen deficiency in males.

Induction of hypogonadism or medical castration is a well-established therapeutic goal in men with recurrent or metastatic hormonally driven prostate cancer. This is typically achieved with androgen deprivation therapy either a GnRH analogue or androgen receptor blockade. Over half of men receiving ADT for treatment of prostate cancer experience metabolic syndrome. These men represent an excellent biological model for studying the association between hypogonadism and metabolic syndrome however research to date has focused on establishing the association but not the responsible mechanisms.

This study will establish the mechanism of metabolic dysfunction in males with androgen deficiency. Firstly a cohort of men with hypogonadism prior to testosterone replacement will undergo detailed metabolic phenotyping using multiple approaches including metabolomic data from skeletal muscle samples, and metabolic parameters using serum samples. This data will be compared to age and weight matched eugonadal healthy controls before and after testosterone replacement as per routine clinical care. The same detailed metabolic phenotyping will be performed on men with prostate cancer before and after therapeutic induction of hypogonadism.

Our study will provide an unparalleled understanding of the tissue- and sex-specific role of androgens as a driver of metabolic dysfunction. Anticipated disturbances in mitochondrial function and energy biogenesis in androgen excess and deficiency will advance scientific knowledge and create potential for developing future tissue specific mediators of metabolic dysfunction in males with hypogonadism.

Serum Samples for targeted and non targeted metabolomics Saliva samples for targeted metabolomics Urine samples for targeted metabolomics Skeletal muscle samples for non targeted metabolomics

Exploring the Relationship Between Androgen Metabolism, Metabolic Disease and Skeletal Muscle Energy Balance in Men

Differences in non-targeted serum and skeletal muscle metabolomics in men with hypogonadism compared to controls

Differences in non-targeted serum and skeletal muscle metabolomics in men

Differences in steroid metabolomics in men with prostate cancer pre- and post-androgen deprivation therapy (ADT)

Differences in serum, urinary and salivary steroid metabolism

Steroid Metabolism Analysis Core, University of Birmingham

Institute of Systems, Molecular and Integrative Biology, University of Liverpool

Royal College of Surgeons, Ireland

Behaviors and Mental Disorders

Fatigue

Quality of Life

Testosterone 1.62% gel will be applied daily by the participants (all participants will be trained in the application process and will be given printed instructions). The intervention will be for 6 months.

The placebo gel will be applied daily by the participants (all participants will be trained in the application process and will be given printed instructions). The intervention will be for 6 months.

The gel will be applied daily by the participants (all participants will be trained in the application process and will be given printed instructions). The intervention will be for 6 months

testosterone 1.62% gel

placebo gel

Jose Garcia, MD, Phd

Egidio Del Fabbro, MD

Milena Braga, MD

Shehzad Basaria, MD

Haley Lowe, RN, MN

Lindsey Anderson, PhD

Jose M Garcia, MD, PhD

This is a large randomized, double-blind, placebo-controlled trial to determine the efficacy of testosterone replacement on cancer-related fatigue in older men with solid or hematologic (blood) cancer who report fatigue and have low testosterone levels.

The overall objective is to conduct a double-blind, randomized, placebo-controlled, parallel group trial to determine the efficacy of 6 months of physiological testosterone replacement therapy in improving cancer related fatigue, sexual dysfunction, and body composition and muscle function in men 55 years and older with solid or hematologic (blood) cancers, who report fatigue and have testosterone deficiency. There will be 5 study visits: 1) Screening, 2) Baseline, 3) 2-Week Dose Adjustment Visit, 4) Three-month visit (Week 12), and 5) Six-month visit. Testosterone or placebo gels will be applied by eligible trial participants at home; participants will be trained on gel application procedures by research personnel.

randomized, double-blind, placebo-controlled, parallel group, trial of daily transdermal testosterone gel or placebo gel for 6-months

Improving Cancer-related Fatigue, Sexual Dysfunction and Quality of Life in Older Men With Cancer and Androgen Deficiency

Erectile function will be assessed by International Index of Erective Function (IIEF).

Mood and well-being will be assessed by Positive and Negative Affect Scale (PANAS), which includes 10 questions each for Positive Affect and Negative Affect. Many behavioral scientists consider affectivity as the cleanest window on an individual's wellbeing. The most sensitive indicator of impaired wellbeing has been shown to be affective dysregulation, which is reflected in affectivity balance. The latter incorporates negative affects (e.g., anxiety, depression) as well as positive affects (e.g., joy).

Body composition changes will be assessed by measuring lean body mass and fat mass by dual energy X-ray absorptiometry (DEXA).

Muscle strength will be assessed by measuring maximal voluntary strength in the leg press exercise by the 1-RM method.

Physical function will be evaluated using the 6-minute walk test and will also be evaluated by measuring power in the lower extremities by conducting the leg press exercise.

To determine changes in daily physical activity, validated actigraphy will be used.

The Brief Assessment Scale for Caregivers (BASC) will be used to determine caregiver burden.

Loss of productivity will be evaluated using the Work Productivity and Impairment (WPAI) scale.

Sleep quality will be assessed using the validated Pittsburgh Sleep Quality Index (PSQI) scale and by using actigraphy.

Qualitative interviews will be performed by a study co-investigator which will assess lived experiences of participants at baseline and at 24 weeks by conducting semi-structured, qualitative phone interviews with a randomly selected sample of 30 men in the testosterone arm and 30 men in the placebo arm (equally divided across the 3 sites).

Primary outcome is change in fatigue score. Fatigue will be assessed by the Functional Assessment of Chronic Illness Therapy fatigue scale (FACIT-Fatigue)- The FACIT-Fatigue has been widely used in studies related to cancer-related fatigue and is able to detect clinically meaningful differences in fatigue scores in response to treatment. Population norms for the FACIT are also available, facilitating the interpretation of fatigue levels in patient populations. This instrument has been well-validated, is responsive to treatment and more sensitive to change in fatigue than other instruments. Score range: 0-52, the higher the score the better quality of life.

Secondary outcome is change in sexual activity score, assessed by the Harbor-UCLA 7-day Sexual Function Questionnaire.

Seattle Institute for Biomedical and Clinical Research

Principal Investigator

Heart and Blood Diseases

Coronary Artery Disease

Myocardial Ischemia

Coronary Disease

Testicular Neoplasms

Lipid Metabolism Disorders

Ischemia

Heart Diseases

Arteriosclerosis

Arterial Occlusive Diseases

Vascular Diseases

Endocrine Gland Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Male Urogenital Diseases

Testicular Diseases

Antineoplastic Agents

Cisplatin

TCS cured with surgical resection and surveillance (surgical/surveillance, Arm 1)

TCS treat with one or more lines of cisplatin-based chemotherapy

TCS treat with one or more lines of cisplatin-based chemotherapy, and who have undergone bone marrow transplant

Lipid profile

Coronary artery assessment

Hormone levels for hypogonadism

Suparna Clasen, MD MSCE

Balaji Tamarapoo, MD PhD

Julie Lacy, RN

Suparna C Clasen, MD MSCE

Late subclinical cardiovascular disease in testicular cancer survivors exposed to cisplatin-based chemotherapy and bone marrow transplant

Testicular cancer (TC) is diagnosed in young adult males between 18-39 years old. There are late (≥10 years after treatment) atherosclerotic cardiovascular disease (ASCVD) events after cisplatin-based chemotherapy (CBCT) treatment in testicular cancer survivors (TCS), along with heightened rates of hypertension, dyslipidemia, diabetes mellitus, and metabolic syndrome. Early detection of ASCVD to direct preventive measures in young TCS is an unmet need as these patients typically fall short of traditional 40-45-year age-cut offs for ASCVD screening. ASCVD risk will be evaluated in TCS ≥ 10 years after treatment in three groups: 1)TCS exposed to CBCT, 2)TCS exposed to CBCT and bone marrow transplant (BMT), and 3)TCS cured with surgical resection/surveillance. The focus will be on detecting subclinical atherosclerosis in TCS using blood lipid biomarkers and advanced cardiac CT imaging.

Late Subclinical Cardiovascular Disease in Testicular Cancer Survivors

Detection of Late Subclinical Cardiovascular Disease in Testicular Cancer Survivors Exposed to Cisplatin-based Chemotherapy and Bone Marrow Transplant

HDL, LDL, Tg, Cholesterol, Novel Lipid biomarkers using blood draws

Coronary calcium score, coronary artery anatomy and plaque assessment using CT scans

Measurement of residual serum platinum levels

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Exploring the Relationship Between Androgen Metabolism, Metabolic Disease and Skeletal Muscle Energy Balance in Men	NCT05773183	Hypogonadism, M... Testosterone De... Prostate Cancer Androgen Defici... Metabolic Disea... Metabolic Syndr... Metabolic Distu... Obesity Cardiovascular ... NAFLD Diabetes	Testosterone GnRH	18 Years - 60 Years	Royal College of Surgeons, Ireland
Exploring the Relationship Between Androgen Metabolism, Metabolic Disease and Skeletal Muscle Energy Balance in Men	NCT05773183	Hypogonadism, M... Testosterone De... Prostate Cancer Androgen Defici... Metabolic Disea... Metabolic Syndr... Metabolic Distu... Obesity Cardiovascular ... NAFLD Diabetes	Testosterone GnRH	18 Years - 60 Years	Royal College of Surgeons, Ireland
Improving Cancer-related Fatigue, Sexual Dysfunction and Quality of Life in Older Men With Cancer and Androgen Deficiency	NCT04301765	Hypogonadism, M... Cancer Fatigue	testosterone 1.... placebo gel	55 Years -	Seattle Institute for Biomedical and Clinical Research
Late Subclinical Cardiovascular Disease in Testicular Cancer Survivors	NCT05611307	Testicular Canc... Survivorship ASCVD Coronary Artery... Lipid Disorder Hypogonadism, M... Cisplatin Adver... Bone Marrow Tra...	Lipid profile Coronary artery... Hormone levels ...	18 Years - 99 Years	Indiana University

Spots Global Cancer Trial Database for hypogonadism, male