madman
Super Moderator
Background. The role of testosterone in improving sexual symptoms in men with hypogonadism is well known. However, recent studies indicate that testosterone plays an important role in several metabolic functions in males.
Methods. Multiple Pubmed searches were conducted with the use of terms, testosterone, insulin sensitivity, obesity, type 2 diabetes, anemia, bone density, osteoporosis, fat mass, lean mass, body composition. This narrative review is focused on detailing the mechanisms that underlie the metabolic aspects of testosterone therapy in humans.
Results. Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids, and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor β subunit, insulin receptor substrate (IRS)-1, AKT-2, and Glucose transporter type 4 (GLUT-4) in adipose tissue and adenosine 5’-monophosphate-activated protein kinase (AMPK) expression and activity in skeletal muscle. Observational studies show that long term therapy with testosterone prevents progression from prediabetes to diabetes and improves hemoglobin A1c. Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor-2, and decreases expression of muscle growth suppressors, myostatin, and Mrf4. Testosterone increases hematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on the bone.
Conclusions. Testosterone exerts a series of potent metabolic effects which include insulin sensitization, maintenance, and growth of the skeletal muscle, suppression of the adipose tissue growth, and maintenance of erythropoiesis and hematocrit.
Testosterone, the major male hormone, has well-established functions as a hormone regulating sexual function, including sexual performance, erectile function, and libido (1). However, it also regulates other functions including muscle mass and muscle strength. This property has been abused by bodybuilders, weightlifters, and athletes for a long time. In addition, it is known that testosterone deficiency leads to anemia, and testosterone therapy increases hemoglobin concentrations (2). It is known that males with hypogonadism suffer from osteoporosis which also improves with testosterone treatment (3). In addition, it has been shown that the hypogonadal state in males is associated with insulin resistance and that testosterone replacement restores insulin sensitivity (4). Clearly, therefore, testosterone has multiple metabolic functions beyond sexual function. This review covers these areas and the recently discovered molecular mechanisms involved underlying these functions.
*Insulin sensitivity
*Diabetes and Prediabetes
*Loss of adiposity
*Role of estrogens in regulating body fat in males
Estrogens have a role in mediating the anti-obesity effects of testosterone. Estrogen receptor deletion in mice leads to weight gain and obesity (49). Men rendered hypogonadal with injections of depot gonadotropin-releasing hormone agonist lose fat when given testosterone, but they do not lose body fat if they are treated with an aromatase inhibitor which is responsible for converting testosterone to estradiol (50). These findings are consistent with the observation that hormone replacement therapy in women leads to less weight gain after menopause. In this context, it is relevant that male patients with diabetes have diminished expression of estrogen receptor and aromatase, both of which are restored following testosterone replacement (51). Consistent with these observations, estradiol concentrations are low in men with HH and type 2 diabetes, and increase after testosterone administration (52).
*Muscle growth
*Testosterone modulates androgen and estrogen receptor and aromatase expression
The deficiency of a hormone leads to the expectation that there will be a compensatory increase in its receptor expression so as to maximize the effect of the limited hormone available. However, in patients with HH and type 2 diabetes, the expression of the androgen receptor was found to be diminished both in mononuclear cells and in adipose tissue(51). This was also associated with a decrease in the expression of estrogen receptor in the adipose tissue which was again contrary to expectations since estradiol concentrations were also diminished in these patients. In addition, there was also a reduction in the expression of aromatase, the enzyme which converts testosterone to estradiol. Testosterone replacement led to the increase/restoration of androgen receptor, estrogen receptor, and aromatase. The men with hypogonadism also had a lower protein content of the androgen receptor in the total cell lysates of skeletal muscle and in the nuclei of mononuclear cells. There was an increase in the androgen receptor following testosterone therapy. Thus, the state of HH leads not only to a lack of testosterone and estradiol but also to a deficiency in their respective receptors and thus possibly the ability of the patient to respond to these hormones. Testosterone replacement reverses these defects to potentially restore these actions. It appears that the tissue androgen and estrogen receptors follow the availability of their ligands: decreasing in the hormone-deficient state and increasing in the hormone replete state. It is not known if these changes have a role in mediating the signs and symptoms of hypogonadism and the response to hormone replacement therapy.
*Hematocrit
*Bone Growth
*Androgen deprivation therapy
Concerns with testosterone treatment
Concerns regarding testosterone replacement therapy in elderly men generally relate to prostate hypertrophy, prostate cancer, cardiovascular events, erythropoiesis leading to polycythemia, lowering of HDL cholesterol, and fluid retention.
*Prostate
*Erythrocytosis
*Cardiovascular events and testosterone therapy
*Other side effects of testosterone therapy
In conclusion, testosterone exerts a series of potent metabolic effects which include insulin sensitization, the maintenance and growth of the skeletal muscle, the suppression of the adipose tissue growth, the maintenance and growth of the skeletal mass, and the maintenance of erythropoiesis and the hematocrit. It is not surprising, therefore, that testosterone deficiency leads to a series of clinical effects including insulin resistance, anemia, adiposity, loss of muscle, and bone loss. The replacement of testosterone leads to the reversal of these features.
Methods. Multiple Pubmed searches were conducted with the use of terms, testosterone, insulin sensitivity, obesity, type 2 diabetes, anemia, bone density, osteoporosis, fat mass, lean mass, body composition. This narrative review is focused on detailing the mechanisms that underlie the metabolic aspects of testosterone therapy in humans.
Results. Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids, and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor β subunit, insulin receptor substrate (IRS)-1, AKT-2, and Glucose transporter type 4 (GLUT-4) in adipose tissue and adenosine 5’-monophosphate-activated protein kinase (AMPK) expression and activity in skeletal muscle. Observational studies show that long term therapy with testosterone prevents progression from prediabetes to diabetes and improves hemoglobin A1c. Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor-2, and decreases expression of muscle growth suppressors, myostatin, and Mrf4. Testosterone increases hematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on the bone.
Conclusions. Testosterone exerts a series of potent metabolic effects which include insulin sensitization, maintenance, and growth of the skeletal muscle, suppression of the adipose tissue growth, and maintenance of erythropoiesis and hematocrit.
Testosterone, the major male hormone, has well-established functions as a hormone regulating sexual function, including sexual performance, erectile function, and libido (1). However, it also regulates other functions including muscle mass and muscle strength. This property has been abused by bodybuilders, weightlifters, and athletes for a long time. In addition, it is known that testosterone deficiency leads to anemia, and testosterone therapy increases hemoglobin concentrations (2). It is known that males with hypogonadism suffer from osteoporosis which also improves with testosterone treatment (3). In addition, it has been shown that the hypogonadal state in males is associated with insulin resistance and that testosterone replacement restores insulin sensitivity (4). Clearly, therefore, testosterone has multiple metabolic functions beyond sexual function. This review covers these areas and the recently discovered molecular mechanisms involved underlying these functions.
*Insulin sensitivity
*Diabetes and Prediabetes
*Loss of adiposity
*Role of estrogens in regulating body fat in males
Estrogens have a role in mediating the anti-obesity effects of testosterone. Estrogen receptor deletion in mice leads to weight gain and obesity (49). Men rendered hypogonadal with injections of depot gonadotropin-releasing hormone agonist lose fat when given testosterone, but they do not lose body fat if they are treated with an aromatase inhibitor which is responsible for converting testosterone to estradiol (50). These findings are consistent with the observation that hormone replacement therapy in women leads to less weight gain after menopause. In this context, it is relevant that male patients with diabetes have diminished expression of estrogen receptor and aromatase, both of which are restored following testosterone replacement (51). Consistent with these observations, estradiol concentrations are low in men with HH and type 2 diabetes, and increase after testosterone administration (52).
*Muscle growth
*Testosterone modulates androgen and estrogen receptor and aromatase expression
The deficiency of a hormone leads to the expectation that there will be a compensatory increase in its receptor expression so as to maximize the effect of the limited hormone available. However, in patients with HH and type 2 diabetes, the expression of the androgen receptor was found to be diminished both in mononuclear cells and in adipose tissue(51). This was also associated with a decrease in the expression of estrogen receptor in the adipose tissue which was again contrary to expectations since estradiol concentrations were also diminished in these patients. In addition, there was also a reduction in the expression of aromatase, the enzyme which converts testosterone to estradiol. Testosterone replacement led to the increase/restoration of androgen receptor, estrogen receptor, and aromatase. The men with hypogonadism also had a lower protein content of the androgen receptor in the total cell lysates of skeletal muscle and in the nuclei of mononuclear cells. There was an increase in the androgen receptor following testosterone therapy. Thus, the state of HH leads not only to a lack of testosterone and estradiol but also to a deficiency in their respective receptors and thus possibly the ability of the patient to respond to these hormones. Testosterone replacement reverses these defects to potentially restore these actions. It appears that the tissue androgen and estrogen receptors follow the availability of their ligands: decreasing in the hormone-deficient state and increasing in the hormone replete state. It is not known if these changes have a role in mediating the signs and symptoms of hypogonadism and the response to hormone replacement therapy.
*Hematocrit
*Bone Growth
*Androgen deprivation therapy
Concerns with testosterone treatment
Concerns regarding testosterone replacement therapy in elderly men generally relate to prostate hypertrophy, prostate cancer, cardiovascular events, erythropoiesis leading to polycythemia, lowering of HDL cholesterol, and fluid retention.
*Prostate
*Erythrocytosis
*Cardiovascular events and testosterone therapy
*Other side effects of testosterone therapy
In conclusion, testosterone exerts a series of potent metabolic effects which include insulin sensitization, the maintenance and growth of the skeletal muscle, the suppression of the adipose tissue growth, the maintenance and growth of the skeletal mass, and the maintenance of erythropoiesis and the hematocrit. It is not surprising, therefore, that testosterone deficiency leads to a series of clinical effects including insulin resistance, anemia, adiposity, loss of muscle, and bone loss. The replacement of testosterone leads to the reversal of these features.
