Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Gland and Hormone Related Diseases

Prostatic Neoplasms

Hypogonadism

Gonadal Disorders

Endocrine System Diseases

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Methyltestosterone

Testosterone

Testosterone undecanoate

Testosterone enanthate

Testosterone 17 beta-cypionate

Androgens

Hormones

Hormone Antagonists

Daily application of two pump auctions of 16.2mg/ml testosterone gel. Dosage may be altered depending on clinical response

Daily application of two pump auctions of placebo gel.

Testosterone gel

Placebo

Joost van Drumpt, MSc

Rob Wijn, MD

Pim van Leeuwen, MD, PhD

Eric Vrijhof, MD, PhD

Max Bruins, MD, PhD

Harm van Melick, MD, PhD

Jean-Paul van Basten, MSc, PhD

Michiel Sedelaar, MD, PhD

Diederik Somford, MD, PhD

Sexual dysfunction is a common side effect of radical prostatectomy (RP) and has a significant negative impact on quality of life. With age the testosterone level in men declines; around 30% of men over 70 years of age meet the criteria of testosterone deficiency (TD). The negative impact of both TD and RP on sexual performance are likely to add up. The aim of this study is to assess the efficacy and safety of testosterone replacement therapy (TRT) on functional and oncological outcomes in testosterone deficient men following RP for prostate cancer (PCa).

Rationale: Radical prostatectomy (RP) is currently the most common treatment for non-metastatic prostate cancer (PCa). Two frequent side effects of this procedure are urinary incontinence and erectile dysfunction, both having a significant negative impact on quality of life.

Additionally, it is known that with age the testosterone level in men declines. This does not lead to symptoms in all men (asymptomatic testosterone deficiency). Both testosterone deficiency (TD) and radical prostatectomy are well-established to have a significant negative impact on sexual performance and are likely to add up in patients with a low testosterone following RP.

Objective: The aim of this study is to assess the effect of testosterone replacement therapy (TRT) on functional and oncological outcomes in testosterone deficient men following RP for PCa.

Study design: This study is a phase 3 prospective, randomized, placebo-controlled, single-blind clinical trial. Study population: All men over 18 years old diagnosed with non-metastatic prostate cancer who are scheduled for RP within three months as primary treatment, can be prescreened for inclusion. Prior to the RP, serum testosterone will be determined. Subsequently, within six weeks after the RP, serum testosterone will be determined again and patients will be screened for inclusion. If necessary, a third measurement of testosterone will be done. Eligible patients meet the criteria for TD and other inclusion criteria. Intervention: Patients will be randomized for testosterone replacement therapy (TRT) or placebo as a daily administered topical gel starting within 8 weeks after RP. Patients will receive TRT or placebo for one year following RP and will be monitored for another year for functional outcomes and for four more years to establish 5-year biochemical recurrence (BCR) free survival.

Main study parameters/endpoints:

The primary study endpoint is a clinically relevant (12 points or more) difference in the EPIC-26 domain for sexual functioning 12 months after RP in favor of testosterone deficient men receiving TRT compared with testosterone deficient men receiving placebo. Secondary endpoints include: urinary incontinence score, hormonal functioning score and BCR-free survival. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The number of visits and blood drawings are equal to standard of care follow-up after RP, with the exception of two or three extra blood samples at the first prescreening visit and within six weeks following RP. We ask patients to remain with their hospital for 24 months after RP for follow-up and to complete online questionnaires for the given visits. The five-year biochemical recurrence (BCR) free survival will be obtained through patient's medical records and if insufficient, through the Dutch Cancer Registry (NKR). Patients who receive TRT or placebo can experience local side-effects such as itching, rash and/or irritation at the site of application. In addition, patients who receive TRT can experience systemic sideeffects are gain of weight, hot flashes, acne and an increase in red blood count level. Furthermore, TRT might improve sexual functioning, urinary continence, hormonal functioning and BCR-free survival, but this is not certain and is subject of research in this study.

Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy

Functional recovery after radical prostatectomy will be assessed by EPIC-26 questionnaire, a Patient Reported Outcome Measure (PROM). Patients will be asked to complete this questionnaire online.

Clinical relevance (\>12 points) for sexual function domain score as measured by EPIC-26.

Clinical relevance (\>9 points) for Urinary incontinence domain score as measured by EPIC-26.

Clinical relevance (\>6 points) for hormonal functioning domain score as measured by EPIC-26.

Biochemical recurrence (BCR) is defined as the occurrence of measurable (\>0.1 ng/ml) prostate specific antigen (PSA), during routinely follow-up up to five years after surgery, determined at two different occasions with at least one week between them.The BCR-rate between the placebo and control group will be compared to determine the influence of testosterone therapy on BCR.

Besins Healthcare

Canisius-Wilhelmina Hospital

Uterine Cervical Neoplasms

Premature Birth

Primary Ovarian Insufficiency

Menopause, Premature

Menopause

Reproductive Control Agents

Estradiol

Estrogens

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Polyestradiol phosphate

Antineoplastic Agents, Hormonal

Anabolic Androgenic Steroids

Anabolic Agents

Subdermal implant-bioabsorbable testosterone pellet (100 mg of testosterone)

Subdermal implant-bioabsorbable placebo pellet (cholesterol)

Intervention arm: Subdermal implant-bioabsorbable testosterone pellet (100 mg of testosterone)

testosterone pellet (100 mg)

André Malavasi, PhD

Edmund Baracat, PhD

Estrogen and androgen deficiencies negatively impact the quality of life of women at different stages of life, especially after menopause. New modalities and new therapeutic alternatives have been researched. Parenteral administration of estradiol and testosterone could be effective to treat symptoms secondary to estrogen and androgen deficiencies and minimize these adverse events. This study evaluates the efficiency of subdermal implant-bioabsorbable use in women with menopausal symptoms associated with secondary estrogen and androgen deficiencies in women with natural menopause, premature ovarian failure or surgical menopause due to cervical cancer. Pharmacokinetic, biochemical, metabolic, thromboembolic and hormonal data will be evaluated, as well as the effects on quality of life, menopausal symptoms and sexual function after treatment.

The clinical study will be carried out on 140 women, who will be divided into three groups: (1) postmenopausal women with menopausal and sexual symptoms (n=60); (2) women with premature ovarian failure (n=40); (3) women with cervical cancer undergoing abdominal hysterectomy with bilateral adnexectomy, with menopausal and sexual symptoms (n=40).

All participants will answer questionnaires to assess quality of life, menopausal symptoms and sexual function. All participants will undergo general physical and gynecological examinations, as well as hormonal, biochemical, thromboembolic and imaging tests.

The study will last six months. The included participants will undergo the following visits: inclusion (post-selection) and 1, 3 and 6 months after implant insertion. For the pharmacokinetic study, blood samples will be collected at the following periods: inclusion (before implant placement) and after 1h, 2h, 3h, 6h and 12h; one week, two weeks and one month after placement, and then monthly until six months after implant insertion, to evaluate serum levels of Luteinizing hormone, Follicle stimulating hormone, estradiol, estrone, total testosterone and sex hormone-binding globulin.

Clinical, biochemical, hormonal and therapeutic parameters will be evaluated before placement (inclusion) and after 3 and 6 months. The Mann Whitney test will be applied to evaluate differences between measurements and the chi-square test will be applied to analyze the proportions of improvement between groups before and after treatment.

Estradiol and Testosterone Subdermal Implants for Menopause Treatment (ESTIME)

Pharmacokinetic, Clinical, Hormonal and Therapeutic Effects of the Use of Estradiol and Testosterone Hormonal Subdermal Implants in Women With Natural Menopause, Premature Ovarian Failure or Surgical Menopause Due to Cervical Cancer.

evaluate concentration in serum of luteinizing hormone, follicle stimulating hormone, estradiol, estrone, total testosterone and sex hormone-binding globulin.

Evaluate response on vulvovaginal atrophy and genitourinary syndrome of menopause, hormonal and metabolic effects on climacteric symptoms, using the Kupperman Menopausal Index; response in quality of life and sexual function; hormonal and metabolic effects;

University of Sao Paulo General Hospital

Professor

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Diabetes Mellitus

Syndrome

Obesity

Metabolic Syndrome

Metabolic Diseases

Eunuchism

Insulin Resistance

Hyperinsulinism

Glucose Metabolism Disorders

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy	NCT04833426	Prostatic Neopl... Hypogonadism Testosterone De...	Testosterone ge... Placebo	18 Years -	Canisius-Wilhelmina Hospital
Estradiol and Testosterone Subdermal Implants for Menopause Treatment (ESTIME)	NCT06343870	Menopause Testosterone De... Estrogen Defici...	testosterone pe... Placebo	18 Years - 60 Years	University of Sao Paulo General Hospital
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
Estradiol and Testosterone Subdermal Implants for Menopause Treatment (ESTIME)	NCT06343870	Menopause Testosterone De... Estrogen Defici...	testosterone pe... Placebo	18 Years - 60 Years	University of Sao Paulo General Hospital
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

Spots Global Cancer Trial Database for testosterone deficiency