Exploring the Relationship Between Androgen Metabolism, Metabolic Disease and Skeletal Muscle Energy Balance in Men
NCT ID: NCT05773183
Last Updated: 2023-03-17
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
60 participants
OBSERVATIONAL
2023-03-12
2024-08-31
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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CASE_CROSSOVER
PROSPECTIVE
Study Groups
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OBS1 [Observational Cohort 1]
20 Eugonadal Healthy men 20 Men with Testosterone Deficiency not currently on Testosterone replacement therapy
No interventions assigned to this group
IC1 [Interventional Cohort 1]
20 Men with Testosterone Deficiency progressed from OBS1 6 months post initiation of testosterone replacement therapy
Testosterone
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
IC2 [Interventional Cohort 2]
20 men with prostate cancer planned for GnRH analogue therapy
GnRH
20 men in OBS2 planned for GnRH analogue therapy will undergo data collection prior, and 3 months post initiation of GnRH analogue therapy
Interventions
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Testosterone
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
GnRH
20 men in OBS2 planned for GnRH analogue therapy will undergo data collection prior, and 3 months post initiation of GnRH analogue therapy
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Ages 18 - 60 years
* BMI 20 - 35 kg / m2
* Able to provide consent
* Ages 40-85 years
* BMI 20 - 35 kg / m2
Exclusion Criteria
* BMI \<20 or \> 35 kg / m2
* Age \< 18 or \> 60 years
* Diabetes Mellitus
* Confirmed ischaemic heart disease
* In patients with secondary hypogonadism co-existence of any untreated pituitary hormone deficiencies (ACTH, TSH, GH deficiency)
* Glucocorticoid use via any route within the last three months
* Current intake of drugs known to impact upon steroid or metabolic function or intake of such drugs during the six months preceding the planned recruitment
* Diabetes mellitus
* Confirmed ischaemic heart disease
* Any glucocorticoid therapy in the last 3 months (inhaled/transdermal/systemic)
* BMI \<20 or \>35
* Pre-existing hormonal pathology - primary testicular or pituitary pathology
* Age \<40 or \>85
18 Years
60 Years
MALE
Yes
Sponsors
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Steroid Metabolism Analysis Core, University of Birmingham
UNKNOWN
University of Liverpool
OTHER
Royal College of Surgeons, Ireland
OTHER
Responsible Party
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Locations
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Beaumont Hospital
Dublin, , Ireland
Countries
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Central Contacts
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Facility Contacts
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Other Identifiers
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MMetDMH
Identifier Type: -
Identifier Source: org_study_id
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