Mechanisms Underlying the Metabolic Actions of T in the Human

[madman]

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.

 

[madman]

Table 1: Metabolic effects of testosterone in males. “+” symbols in column 2 indicate the strength of evidence. “++” indicates that the effect is consistently observed in multiple randomized controlled trials (RCTs) while “+” indicates that the effect is observed in many, but not all RCTs. Mrf4 (myogenic regulatory factor 4) FFA (Free fatty acids)

 

[madman]

Figure 1: Insulin sensitivity, expressed as glucose infusion rate during hyperinsulinemic-euglycemic clamps, after treatment with intramuscular testosterone or saline (placebo) for 24 weeks in men with hypogonadism and type 2 diabetes. Bars represent means ±S.D. The figure is based on data published in Diabetes Care (4). *P=0.002 by t-test for change at 24 weeks as compared to placebo.

 

[madman]

Figure 2: Cellular effects of testosterone that contribute to increasing insulin signaling and glucose uptake. Mechanisms noted in various tissues are depicted in a combined manner in the figure. Stimulatory effects of testosterone are shown as “+” in green square and inhibitory effects are shown as “-” in a red oval shape. “+” or “-” in white ovals depict the effects of insulin signaling mediators other than testosterone. It is not known how the stimulatory effect of testosterone therapy on androgen receptor expression and protein is linked to the mechanisms shown in the figure. Abbreviations: inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β), Suppressor of cytokine signaling (SOCS)-3, Phosphatase and tensin homolog (PTEN), protein-tyrosine phosphatase 1B (PTP-IB), Toll-like receptor (TLR)-4, Insulin receptor (IR), insulin receptor substrate (IRS), Protein kinase B (AKT), Glucose transporter type 4 (GLUT-4), Free fatty acids (FFA), Phosphoinositide 3-kinases (PI3K), adenosine 5’-monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3,4,5 trisphosphate (PIP3), 3- phosphoinositide-dependent protein kinase-1 (PDK1), Akt substrate (AS) 160, Rab (G protein member of Ras superfamily)

 

[madman]

Hematocrit

The stimulatory effect of testosterone on hematocrit has been known for a long time (59). Hypogonadal states are characterized by a mild normocytic normochromic anemia which reverses following testosterone treatment (2). The mechanism underlying this effect has been thought to be due to an increase in erythropoietin synthesis in the kidney. However, more recently, it has been shown that hepcidin concentration is suppressed by testosterone (60, 61). Hepcidin suppresses the expression of ferroportin, the membrane protein responsible for the absorption of iron by the enterocyte, and the release of iron stored in the monocytes and macrophages of the reticuloendothelial system (62). Thus ferroportin has a cardinal role in increasing the bio-availability of iron. Recent investigations have also revealed that with the suppression of hepcidin, testosterone therapy increases the expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations (63). Plasma iron and ferritin concentrations fall. These findings are consistent with the release of iron from the stores with an increase in ferroportin and the transport of iron to erythropoietic cells through transferrin and the uptake of iron by erythropoietic tissues through the transferrin receptor. These effects, in addition to the stimulatory effect of testosterone on erythropoietin production, enhance hemoglobin production following testosterone therapy.






Erythrocytosis: Erythrocytosis is a known adverse effect of testosterone administration. A randomized placebo-controlled trial of transdermal testosterone therapy for one year in elderly men found a 2% incidence of polycythemia (2). The effect is dose-dependent and is seen more commonly in those with supra-normal levels of testosterone. Hematocrit above 55% increases blood viscosity and could exacerbate vascular disease in the coronary, cerebrovascular, or peripheral vascular circulation. Periodic hematological assessment is therefore indicated (1). In those with other causes of secondary polycythemia (such as smoking or sleep apnoea), dose adjustment and/or periodic phlebotomy may be necessary to keep the hematocrit below 55%.

 

[madman]

Other side effects of testosterone therapy: There is a risk for gynecomastia in the first few months after the initiation of testosterone therapy. A decrease in testicular size, spermatogenesis, and compromised fertility can occur during testosterone therapy can occur because of the down regulation of gonadotropins(1). Specific to men using transdermal gels for testosterone therapy, there is a possibility of transferring the drug to others after skin-to-skin contact. Testosterone is anabolic and it can cause retention of sodium and water. Edema may be worsened in patients with pre-existing cardiac, renal, or hepatic disease. Testosterone therapy should be avoided in men with decompensated heart failure (1).

Of note, testosterone therapy in men with compensated heart failure does not worsen ejection fraction and seems to improve physical performance (measured by distance walked before the onset of shortness of breath) (58). In general, the administration of testosterone in supraphysiological doses is more likely to lead to polycythemia, fluid retention, and decrease in HDL cholesterol, and whereas the physiological replacement is usually not accompanied by these effects (100).