Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05773183 |
| Other study ID # |
MMetDMH |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 12, 2023 |
| Est. completion date |
August 2024 |
Study information
| Verified date |
December 2022 |
| Source |
Royal College of Surgeons, Ireland |
| Contact |
Michael O' Reilly, FRCPI PhD |
| Phone |
018093894 |
| Email |
michaelworeilly[@]rcsi.ie |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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.
Description:
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.
