|

 

Are the adverse effects of glitazones linked to induced testosterone deficiency?

Center for Sexual Medicine Center for Sexual Medicine Papers Are the Adverse Effects ofGlitazones Linked to InducedTestosterone Deficiency? Carruthers, M, TR Trinick, E Jankowska, AM Traish. "Are the adverse effects ofglitazones linked to induced testosterone deficiency?" Cardiovascular Diabetology7:30. (2008)http://hdl.handle.net/2144/2660Boston University Hypothesis
Are the adverse effects of glitazones linked to induced testosterone
deficiency?
M Carruthers*1, TR Trinick2, E Jankowska3,4,5 and AM Traish6
Address: 1Centre for Men's Health, 20/20 Harley Street, London, UK, 2Department of Chemical Pathology, The Ulster Hospital, Belfast, (TRT) UK, 3Cardiology Department, Military Hospital, Wroclaw, Poland, 4Institute of Anthropology, Polish Academy of Sciences, Wroclaw, Poland, 5National Heart and Lung Institute, Imperial College, London, (EJ) UK and 6Institute for Sexual Medicine, Boston University School of Medicine, Center for Advanced Biomedical Research, Boston, (AMT) USA Email: M Carruthers* - [email protected]; TR Trinick - [email protected]; E Jankowska - [email protected]; AM Traish - [email protected] * Corresponding author Published: 15 October 2008 Received: 12 August 2008Accepted: 15 October 2008 Cardiovascular Diabetology 2008, 7:30
2008 Carruthers et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Adverse side-effects of the glitazones have been frequently reported in both clinical and
animal studies, especially with rosiglitazone (RGZ) and pioglitazone (PGZ), including congestive heart
failure, osteoporosis, weight gain, oedema and anaemia. These led to consideration of an evidence-based
hypothesis which would explain these diverse effects, and further suggested novel approaches by which
this hypothesis could be tested.
Presentation of hypothesis: The literature on the clinical, metabolic and endocrine effects of glitazones
in relation to the reported actions of testosterone in diabetes, metabolic syndrome, and cardiovascular
disease is reviewed, and the following unifying hypothesis advanced: "Glitazones induce androgen deficiency
in patients with Type 2 Diabetes Mellitus resulting in pathophysiological changes in multiple tissues and organs
which may explain their observed clinical adverse effects." This also provides further evidence for the
lipocentric concept of diabetes and its clinical implications.
Testing of the hypothesis: Clinical studies to investigate the endocrine profiles, including
measurements of TT, DHT, SHBG, FT and estradiol, together with LH and FSH, in both men and women
with T2DM before and after RGZ and PGZ treatment in placebo controlled groups, are necessary to
provide data to substantiate this hypothesis. Also, studies on T treatment in diabetic men would further
establish if the adverse effects of glitazones could be reversed or ameliorated by androgen therapy. Basic
sciences investigations on the inhibition of androgen biosynthesis by glitazones are also warranted.
Implications of the hypothesis: Glitazones reduce androgen biosynthesis, increase their binding to
SHBG, and attenuate androgen receptor activation, thus reducing the physiological actions of
testosterone, causing relative and absolute androgen deficiency. This hypothesis explains the adverse
effects of glitazones on the heart and other organs resulting from reversal of the action of androgens in
directing the maturation of stem cells towards muscle, vascular endothelium, erythroid stem cells and
osteoblasts, and away from adipocyte differentiation. The higher incidence of side-effects with RGZ than
PGZ, may be explained by a detailed study of the mechanism by which glitazones down-regulate androgen
biosynthesis and action, resulting in a state of androgen deficiency.
(page number not for citation purposes)

Cardiovascular Diabetology 2008, 7:30
glitazones give rise to a unifying hypothesis based on Recent clinical studies have raised serious concerns reduction of testosterone biosynthesis and function regarding the safety of glitazones, especially rosiglitazone(RGZ) and pioglitazone (PGZ) to regulate hyperglycemia Presentation of hypothesis
in diabetic patients. A meta-analysis study ] demon- A Unifying Hypothesis Linking the Adverse Effects of
strated use of RGZ was associated with a "significant Glitazones to Induced Testosterone Deficiency
increase in the risk of myocardial infarction and with an We advance the following unifying hypothesis: "Glitazones increase in the risk from cardiovascular causes that had border- induce androgen deficiency in patients with Type 2 Diabetes line significance". These side effects were confirmed by Mellitus resulting in pathophysiological changes in multiple tis- other clinical studies[ and meta-analysehough sues and organs which may explain their observed clinical some investigators, particularly those reporting the effects adverse effects of PGZ treatm reductions in cardiacdeaths.
It also provides further evidence for Ungar's theory of the'Lipocentric Pathway to Hyperglycemia', and explains the Because of the widespread use of glitazones, it is of con- toxic ectopic fat distribution in multiple organs, together siderable practical importance to understand the potential with its clinical implications mechanisms underlying the differing effects of these twothiazolidines on clinical endpoints, in spite of their appar- Evidence Supporting this Hypothesis
ent similar effectiveness in reducing blood glucose, as well A. Epidemiological Studies as their wide range of adverse side-effects, including There is increasingly considered that low T levels in men weight gain, anaemia and osteoporosis. These links play an important role in the causation of T2DM, and are between the clinical, metabolic and endocrine effects of associated with reduced insulin sensitivity n men, cir-culating T is inversely related to classical cardiovascular Unifying hypothesis linkin g 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 Bind-
ing 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 produc-
tion and action, with adverse clinical side-effects.
(page number not for citation purposes)

Cardiovascular Diabetology 2008, 7:30
disease (CVD) risk factors, including dyslipidaemia, C. Treatment in Men hypertension, pro-thrombotic and pro-inflammatory Treatment of diabetic men with T has many beneficial states, insulin resistance, obesity, abdominal fat distribu- effects, including increasing insulin sensitivity, correcting tion, endothelial dysfunction, intima-media thickness of abnormalities in lipid metabolism, especially hypertrig- the carotid artery and thoracic aorta [ with cor- lyceridaemia, reducing visceral adiposity, decreasing lep- onary artery disease (CAD) confirmed by angiography tin and adiponectin levels, reversing neuropathy, and have a markedly reduced level of circulating T as com- improving erectile function. These effects are largely pared to those with normal coronary ar].
brought about by reducing the adverse metabolic effectsof increased adipose tissue in organs throughout the B. Suppression Therapy body, but particularly in abdominal fat, reversing the Management of prostate cancer via androgen-deprivation actions of the adipocyte as the 'axis of evil' ) [ therapy with surgical or medical castration rapidly Beneficial clinical anti-ischaemic effects of T treatment in induces diabetes in susceptible individuals and is associ- men with angina pectoris were reported as early as in the ated with card. Androgen suppres- 1940te T administration reduces exercise- sion therapy for prostate cancer has been linked to an induced myocardial ischaemia in men with CAD and low increased incidence of coronary heart disease and risk fac- serum testosterone, also prolonging time to ST-segment tors for atherosclerosis [].
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.
(page number not for citation purposes) Cardiovascular Diabetology 2008, 7:30
D. Effects on Muscle and Adipocytes action on erythropots with diabetes tend Singh et al [ suggested that androgens regulate the dif- to be anaemic, especially the elderly, and their low T is ferentiation of multipotent stem cells into the myogenic correlated with their reduced haemreatment lineage and inhibit adipogenesis. They also showed that T with RGZ and PGZ makes them more anaemic, which is inhibited adipogenic differentiation of pre-adipocytes by probably related to lower T levels, not haemodilution activation of androgen receptor (AR)/beta-catenin interac- tion and translocation of androgen receptor/beta catenincomplex to the nucleus, thus bypassing canonical Wnt sig- G. Effects on Bone nalling. These changes can affect all 3 forms of muscle: Because osteoblasts and marrow adipocytes are derivedfrom a common mesenchymal progenitor, increased adi- Smooth muscle pogenesis may occur at the expense of osteoblasts, leading Ultrastructural studies by Traish et al have documented to bone loss. RGZ and PGZ usage were associated with that trabecular smooth muscle from castrated animals more than doubling of fractures of the hip and wrist, appears disorganized, with large number of cytoplasmic increasing with the dose of either thiazolidin vacuoles and a decrease in myofilaments. Androgen dep-rivation in the animal model results in accumulation of Potential Mechanisms of Glitazone-Induced Androgen
adipocytes in penile tissues, particularly in the sub-tunical re]. T replacement restores normal cavernosal his- The actions of the glitazones on reductions in both TT and tological appearance. Recently, Kova] have DHT have been shown in healthy men roglitazone shown that treatment of obese diabetic Zucker fa/fa rats (TGZ) interferes with the activity of the P450 cytochrome with PGZ produced globular fat-like cells in the corpus oxidase (CPY) enzymes and was taken off the market in cavernosum especially at high doses. These observations the USA because of its hepatotoxicity. It also increases sex together suggest a link between the function of anti-dia- hormone binding globulin (SHBG) which redu].
betic agents and interference with T action as shown in As detailed in T either directly, or by its conversion to DHT or estradiol, regulates the differentiation ofmultipotent stem cells into smooth, striated and cardiac Striated Muscle muscle cells, osteoblastic/osteoclastic balance in bone, T increases lean body mass and decreases fat mass in haemopoietic activity, and the formation of cytoskeletal young men, the magnitude of the changes being corre- components [iting the differentiation of lated with T concentrations. Especially in insulin resistant progenitor cells into adipocytes.
diabetes, impaired muscle strength and mass is likely tobe associated with the reduction in myoglobin associated The higher incidence of side-effects with RGZ than PGZ, with low T levels.
may be further explained by a detailed study of the mech-anism by which glitazones down-regulate androgen bio- Cardiac Muscle synthe]. Both RGZ and PGZ changed the steroid Androgen receptors are present in the myocardium (cardi- profile of human adrenal NCI-H295R cells and inhibited omyocytes) and vessel walls[]. Their expression is mod- the activities of P450c17 and 3betaHSDII, key enzymes of ulated by catecholamines and T itself, as shown by its androgen biosynthesis. PGZ but not RGZ inhibited the depletion in hypertrophied and failing hearts, which is expression of the CYP17 and HSD3B2 genes. Likewise, accompanied by deranged intracardiac steroid metabo- PGZ repressed basal and 8-bromo-cAMP-stimulated activ- liseficiency is related to several changes within ities of CYP17 and HSD3B2 promoter reporters in NCI- the myocardium, including impaired contractility of car- H295R cells. However, PGZ did not change the activity of diomyocytes []. All these pathologies can be restored to a cAMP-responsive luciferase reporter, indicating that it normal on T supplementation.
does not influence cAMP/protein kinase A/cAMPresponse element-binding protein pathway signalling.
E. Effects on Endothelial Progenitor CellsT deficiency is associated with a low number of circulating There is also evidence that PGZ, to a greater extent than progenitor cells and endothelial progenitor cells PCs in RGZ, increases the maturation of small adipocytes to young men. T treatment induces an increase in these cells larger ones, promoting a reduction in insulin resist- through a possible direct effect on the bone marrow , decreasing lipogenesis in the liver, and increas-ing deposition of fat in the subcutaneous abdominal F. Effects on Haemopoiesis tissue, but not visceral fat. PGZ showed an additional ben- T treatment increases red blood cell production and hence eficial effect on TG, HDL cholesterol and the levels of haemoglobin and haematocrit either directly by promot- small dense LDL compared to RGZ.
ing erythroid stem cell ki], or indirectly by its (page number not for citation purposes) Cardiovascular Diabetology 2008, 7:30
Testing of hypothesis
on testosterone and CHF, and Mr Stewart McCrea of The Ulster Hospital, Clinical studies are needed to investigate the endocrine Belfast, UK, for the creative artwork in both figures.
profiles, including measurements of TT, DHT, SHBG, FTand oestradiol, together with LH and FSH, in both men Nissen SE, Wolski K: and women with T2DM before and after RGZ and PGZ treatment in double blind, placebo controlled groups.
Engl J Med 2007, 356:2457-2471.
Also, further studies on T treatment in diabetic men Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones would further establish if the adverse effects of glitazones N Engl J Med 2007, could be ameliorated by androgen therapy. Basic sciences investigations on the inhibition of androgen biosynthesis Singh S, Loke YK, Furb JAMA 2007, by glitazones are also warranted.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-BenedettiM, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Implications of the hypothesis
Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine The FDA reports that most PPAR agonists in development RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, are non-thiazolidinediones, and though more than 50 Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, SmithU, Taton J: Innovative New Drug (IND) applications have been filed for this group of drugs in the last seven years, most devel- opment programs have been terminated, all for safety rea- sons, and none have been approved.
Lincoff AM, Wolski K, Nicholls SJ, Niss JAMA 2007, This hypothesis explains the adverse effects of glitazones on the heart and other organs by reducing androgen action in directing stem cells differentiation into myo- JAMA 2008, 299:1185-1187.
Kapoor D, Malkin CJ, Channer KS, Jones TH: cytes, vascular endothelium, erythroid stem cells and oste- Clin Endocrinol (Oxf) oblasts, and promoting adipocyte differentiation. The Choi BG, McLaughlin MA: adverse clinical effects are directly linked to the metabolic Endocrinol Metab Clin North Am actions of these drugs. The higher incidence of side-effects with RGZ compared with PGZ, may be explained by a Beld AW van den, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grob-b detailed study of the mechanism by which glitazones Am J Epidemiol 2003, 157:25-31.
down-regulate androgen biosynthesis and molecular Demirbag R, Yilmaz R, Ulucay A, Unlu D: mechanism of action, resulting in a state of androgen defi- Endocr Res 2005, 31:335-344.
Muller M, Beld AW van den, Bots ML, Grobbee DE, Lamberts SW,Schouw YT van der: Circulation 2004, AR: androgen receptor; CHF: congestive heart failure; Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA CVD: cardiovascular disease; DHT: dihydrotestosterone; FT: free testosterone; IL: interleukin; MI: myocardial inf- Endocrinol Metab 2002, 87:3632-3639.
arction; PCs: progenitor cells; PGZ: pioglitazone; PPAR: English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS: Peroxisome Proliferator-Activated Receptor; RGZ: rosigli- Eur Heart tazone; SHBG: sex hormone binding globulin; T: testo- J 2000, 21:890-894.
sterone; TGZ: Troglitazone; TNF-α: tumour necrosis Phillips GB, Pinkernell BH, Jing TY: Arterioscler factor-alpha; T2DM: Type 2 diabetes mellitus; TT: total Thromb 1994, 14:701-706.
Pugh PJ, Channer KS, Parry H, Downes T, Jone TH: Endocr Res The authors declare that they have no competing interests.
Jones RD, English KM, Pugh PJ, Morice AH, Jones TH, Channer KS: J Cardiovasc Pharmacol 2002, MC conceived the unifying hypothesis. All authors con- Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M,Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P: tributed to the initial manuscript, and revisions were car- ried out by MC and AMT. All authors have read and Circulation 2006, approved the final manuscript.
Tappler B, Katz M: Clin Endocrinol (Oxf) 1979, 10:219-226.
We thank Prof. Piotr Ponikowski and Prof Waldemar Banasiak of the Car- Clin Sci (Lond) 2003, 104:195-201.
diology Department, Military Hospital, Wroclaw, Poland, for their advice (page number not for citation purposes) Cardiovascular Diabetology 2008, 7:30
D'Amico AV, Denham JW, Crook J, Chen MH, Goldhaber SZ, Lamb Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR DS, Joseph D, Tai KH, Malone S, Ludgate C, Steigler A, Kanto Arch Intern Med 2008, Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, J Clin Oncol 2007, 25:2420-2425.
Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G: Niskanen L, Laaksonen DE, Punnonen K, Mustajoki P, Kaukua J, Ris- Diabetes Care Vierhapper H, Nowotny P, Waldhausl W: betes Obes Metab 2004, 6:208-215.
Metabolism 2003, 52:230-232.
Diabetes Care 2001, 24:2149-2151.
J Sex Med Lesser MA: Testosterone propionate therapy in one hundred
cases of angina pectoris. J Clin Endocrinol 1946, 6:549-557.
Kempna P, Hofer G, Mullis PE, Fluck CE Webb CM, Adamson DL, de ZD, Collins P: Mol Pharmacol 2007, Am J Cardiol 1999, 83:437-439.
Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH: McLaughlin T, Sherman A, Tsao P, Gonzalez O, Yee G, Lamendola C, Reaven GM, Cushman SW: Endocrinol Metab 2004, 89:3313-3318.
Diabetologia 2007, Pugh PJ, Jones TH, Channer KS: Eur Heart J Rizzo M, Christ ER, Rini GB, Spinas GA, Berneis K: Malkin CJ, Jones TH, Channer KS: Expert Opin Eur J Heart Fail Piepoli MF, Kaczmarek A, Francis DP, Davies LC, Rauchhaus M,
Jankowska EA, Anker SD, Capucci A, Banasiak W, Ponikowski P:
Circulation 2006,
114:126-134.
Singh R, Artaza JN, Taylor WE, Braga M, Yuan X, Gonzalez-Cadavid
NF, Bhasin S:Endocrinology 2006, 147:141-154.
Traish AM, Kim N: Aging Male 2005, 8:141-146.
Kovanecz I, Ferrini MG, Vernet D, Nolazco G, Rajfer J, Gonzalez-
BJU Int
2006, 98:116-124.
Schock HW, Herbert Z, Sigusch H, Figulla HR, Jirikowski GF, Lotze
U: Horm Metab Res 2006, 38:225-229.
Burtea C, David A, Rom J Endocrinol 1993, 31:41-48.
Golden KL, Marsh JD, Jiang Y, Brown T, Moulden J: Am J Physiol Endocrinol Metab 2003, 285(3):E449-E453.
Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, Garolla
A: J Clin Endocrinol Metab 2006,
91:4599-4602.
Peschle C, Magli MC, Cillo C, Lettieri F, Pizzella F, Migliaccio G, Mas- scientist can read your work free of charge Blood Cells 1978, 4:233-252.
DeLong M, Logan JL, Yong KC, Lien YH "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Nephrol Dial Transplant 2005, 20:585-590.
Bhatia V, Chaudhuri A, Tomar R, Dhindsa S, Ghanim H, Dandona P Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance Berria R, Glass L, Mahankali A, Miyazaki Y, Monroy A, De Filippis E, cited in PubMed and archived on PubMed Central Cusi K, Cersosimo E, Defronzo RA, Gastaldelli A: yours — you keep the copyright ClinPharmacol Ther 2007.
Submit your manuscript here: (page number not for citation purposes)

Source: http://dcommon.bu.edu/bitstream/handle/2144/2660/1475-2840-7-30.pdf?sequence=1&isAllowed=y