Background
Recent clinical studies have raised serious concerns regarding the safety of glitazones, especially rosiglitazone (RGZ) and pioglitazone (PGZ) to regulate hyperglycemia in diabetic patients. A meta-analysis study
Because of the widespread use of glitazones, it is of considerable practical importance to understand the potential mechanisms underlying the differing effects of these two thiazolidines on clinical endpoints, in spite of their apparent similar effectiveness in reducing blood glucose, as well as their wide range of adverse side-effects, including weight gain, anaemia and osteoporosis. These links between the clinical, metabolic and endocrine effects of glitazones give rise to a unifying hypothesis based on reduction of testosterone biosynthesis and function
Presentation of hypothesis
A Unifying Hypothesis Linking the Adverse Effects of Glitazones to Induced Testosterone Deficiency
We advance the following unifying hypothesis: "
Unifying hypothesis linking the adverse effects of glitazones to induced testosterone deficiency
Unifying hypothesis linking the adverse effects of glitazones to induced testosterone deficiency. Testosterone, either directly or by conversion to dihydrotestosterone or oestradiol, all largely regulated by the effect of Sex Hormone Binding Globulin, acts on the Multipotent Stem Cell to promote differentiation to the progenitor cells for muscle, endothelium, bone, and red blood cells. By causing androgen deficiency, glitazones may reverse these effects and promote adipocyte production and action, with adverse clinical side-effects.
It also provides further evidence for Ungar's theory of the 'Lipocentric Pathway to Hyperglycemia', and explains the toxic ectopic fat distribution in multiple organs, together with its clinical implications
Evidence Supporting this Hypothesis
A. Epidemiological Studies
There is increasingly considered that low T levels in men play an important role in the causation of T2DM, and are associated with reduced insulin sensitivity
B. Suppression Therapy
Management of prostate cancer via androgen-deprivation therapy with surgical or medical castration rapidly induces diabetes in susceptible individuals and is associated with cardiovascular events
C. Treatment in Men
Treatment of diabetic men with T has many beneficial effects, including increasing insulin sensitivity, correcting abnormalities in lipid metabolism, especially hypertriglyceridaemia, reducing visceral adiposity, decreasing leptin and adiponectin levels, reversing neuropathy, and improving erectile function. These effects are largely brought about by reducing the adverse metabolic effects of increased adipose tissue in organs throughout the body, but particularly in abdominal fat, reversing the actions of the adipocyte as the 'axis of evil' (Fig
The metabolic and clinical effects of adipocyte activity
The metabolic and clinical effects of adipocyte activity. The adipocyte as the 'Axis of Evil' – PPARγ agonists such as the glitazones stimulate the adipocyte to produce adipocytokines and cause insulin resistance, dyslipidaemias, hypertension, and impaired immunological responses, which together can have the adverse clinical consequences shown.
D. Effects on Muscle and Adipocytes
Singh et al
Smooth muscle
Ultrastructural studies by Traish et al have documented that trabecular smooth muscle from castrated animals appears disorganized, with large number of cytoplasmic vacuoles and a decrease in myofilaments. Androgen deprivation in the animal model results in accumulation of adipocytes in penile tissues, particularly in the sub-tunical region
Striated Muscle
T increases lean body mass and decreases fat mass in young men, the magnitude of the changes being correlated with T concentrations. Especially in insulin resistant diabetes, impaired muscle strength and mass is likely to be associated with the reduction in myoglobin associated with low T levels.
Cardiac Muscle
Androgen receptors are present in the myocardium (cardiomyocytes) and vessel walls
E. Effects on Endothelial Progenitor Cells
T deficiency is associated with a low number of circulating progenitor cells and endothelial progenitor cells PCs in young men. T treatment induces an increase in these cells through a possible direct effect on the bone marrow
F. Effects on Haemopoiesis
T treatment increases red blood cell production and hence haemoglobin and haematocrit either directly by promoting erythroid stem cell kinetics
G. Effects on Bone
Because osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, increased adipogenesis may occur at the expense of osteoblasts, leading to bone loss. RGZ and PGZ usage were associated with more than doubling of fractures of the hip and wrist, increasing with the dose of either thiazolidine
Potential Mechanisms of Glitazone-Induced Androgen Deficiency
The actions of the glitazones on reductions in both TT and DHT have been shown in healthy men
The higher incidence of side-effects with RGZ than PGZ, may be further explained by a detailed study of the mechanism by which glitazones down-regulate androgen biosynthesis
There is also evidence that PGZ, to a greater extent than RGZ, increases the maturation of small adipocytes to larger ones, promoting a reduction in insulin resistance
Testing of hypothesis
Clinical studies are needed to investigate the endocrine profiles, including measurements of TT, DHT, SHBG, FT and oestradiol, together with LH and FSH, in both men and women with T2DM before and after RGZ and PGZ treatment in double blind, placebo controlled groups. Also, further studies on T treatment in diabetic men would further establish if the adverse effects of glitazones could be ameliorated by androgen therapy. Basic sciences investigations on the inhibition of androgen biosynthesis by glitazones are also warranted.
Implications of the hypothesis
The FDA reports that most PPAR agonists in development are non-thiazolidinediones, and though more than 50 Innovative New Drug (IND) applications have been filed for this group of drugs in the last seven years, most development programs have been terminated, all for safety reasons, and none have been approved.
This hypothesis explains the adverse effects of glitazones on the heart and other organs by reducing androgen action in directing stem cells differentiation into myocytes, vascular endothelium, erythroid stem cells and osteoblasts, and promoting adipocyte differentiation. The adverse clinical effects are directly linked to the metabolic actions of these drugs. The higher incidence of side-effects with RGZ compared with PGZ, may be explained by a detailed study of the mechanism by which glitazones down-regulate androgen biosynthesis and molecular mechanism of action, resulting in a state of androgen deficiency.
Abbreviations
AR: androgen receptor; CHF: congestive heart failure; CVD: cardiovascular disease; DHT: dihydrotestosterone; FT: free testosterone; IL: interleukin; MI: myocardial infarction; PCs: progenitor cells; PGZ: pioglitazone; PPAR: Peroxisome Proliferator-Activated Receptor; RGZ: rosiglitazone; SHBG: sex hormone binding globulin; T: testosterone; TGZ: Troglitazone; TNF-α: tumour necrosis factor-alpha; T2DM: Type 2 diabetes mellitus; TT: total testosterone.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MC conceived the unifying hypothesis. All authors contributed to the initial manuscript, and revisions were carried out by MC and AMT. All authors have read and approved the final manuscript.