Improvement of the diabetic foot upon testosterone administration to hypogonadal men with peripheral arterial disease. Report of three cases
© Kalinchenko et al; licensee BioMed Central Ltd. 2009
Received: 28 January 2009
Accepted: 28 March 2009
Published: 28 March 2009
Lower extremity complications (neuropathy, ulceration, infection, and peripheral arterial disease) are common in diabetes mellitus. There is an inverse relation between plasma testosterone and insulin sensitivity, type 2 diabetes mellitus and HbA1c concentrations.
We report the beneficial effects of administration of testosterone to three men with a diabetic foot whose serum testosterone was subnormal.
Upon normalization of serum testosterone there was an improvement of hyperglycemia, a decrease of leukocytes and of fibrinogen levels, an increase of antithrombin III activity and of tissue oxygen pressure. The wound showed granulation.
Beneficial effects of administration of testosterone to hypogonadal with a diabetic foot may be due to improved vascularization and to anti-inflammatory action.
Lower extremity complications are common in patients with diabetes and include neuropathy, ulceration, infection, and peripheral arterial disease. Foot infections represent the single most common cause of hospitalization and lower extremity amputation in persons with diabetes. Foot ulceration as a result of diabetic peripheral sensory neuropathy, rigid osseous deformities and soft-tissue contractures, repetitive trauma from unprotected ambulation, and peripheral vascular disease can all lead to a limb- or even life-threatening infection.
Men with type 2 diabetes have a lower serum testosterone concentration compared to men without a history of diabetes, and there is an inverse association between testosterone levels and HbA1c concentrations. A recent systematic review and meta-analysis of cross-sectional studies indicated that testosterone levels were significantly lower in men with type 2 diabetes. Further, in men with low plasma testosterone the risk of diabetes mellitus is increased. One third to one half of men with type 2 diabetes mellitus are now recognized as testosterone deficient. Emerging evidence suggests that testosterone therapy may be able to reverse some aspects of metabolic syndrome.
Further, a low plasma testosterone level appeared to be associated with endothelial dysfunction in men independent of other risk factors, suggesting a protective effect of endogenous testosterone on the endothelium. In addition, serum endogenous androgen concentrations were inversely associated with arterial stiffness in men with type 2 diabetes mellitus. There is an association of type 2 diabetes with low testosterone values, and therefore, the effects of an intervention with testosterone are of considerable interest. In hypogonadal men, the few studies on the effects of testosterone treatment on glycemic control were divergent. One study replacing testosterone in hypogonadal men with type 2 diabetes found no effect on glycemic control, however another study analyzing 24 hypogonadal men with type 2 diabetes, of which 10 treated with insulin, found that testosterone replacement therapy improved glycemic control confirming an earlier study.
In view of the potential relevance of normalization of plasma testosterone for glycemic control in type 2 diabetes and for vascular function, we undertook a pilot study and administered testosterone to men with a diabetic foot and who were found to have plasma testosterone below the reference range.
All patients received information that they received experimental treatment' to which they consented. This pilot study was approved by the institute's ethical review board. Written informed consent was obtained from each of the patients for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Results of laboratory investigations included hemoglobin (13.1 g/dL), hematocrit (46.6%), leukocytes (9.7 × 109/L), HbA1c (7.4%), fibrinogen (6.8 g/L (normal range 2–4 g/L)), antithrombin III activity (87% (normal range 74%–114%)). Other results of blood chemistry were within normal limits, except for plasma glucose (14.0 mmol/L).
Endocrinological findings: total testosterone (7.2 nmol/L (normal range for adult men 12–35 nmol/L)). Bacteriological culture: growth of epidermal staphylococcus in the wound. Using doppler ultrasound severe stenosis of tibial arteries in the distal part of the right anticnemion was found. X-ray examination did not show signs of osteomyelitis of foot bones. Tissue oxygen tension (TpO2) was 5 mm Hg. Daily treatment included Cefotaxim 2 g, the heparin Fraxiparin 0.6 ml, Vessel Due F 0.5 LPE, dressing of the wound. In addition, one injection of parenteral testosterone undecanoate (TU) (1000 mg) was administered, whereupon plasma levels of total testosterone rose to 20.3 nmol/L.
Results of laboratory investigations while receiving treatment with Netilmicin (0.4 g daily) and fraxiparin (0.6 ml daily): hemoglobin (10.4 g/dL), hematocrit (33.1%), leukocytes (12.2 × 109/L), fibrinogen (5.1 g/L (normal range 2–4 g/L)), antithrombin III activity (74% (normal range 74%–114%)), degree of aggregation – 91.9%, rate of thrombosis – 58%/min. Other blood chemistry tests were within normal limits, with exception of plasma glucose (10 mmol/L). A bacteriological culture revealed bacterial growth in the wound. TpO2 of the foot was 2 mmHg. Plasma testosterone levels were below normal (total testosterone 10.5 nmol/L and even more so of bioavailable testosterone: 2.58 nmol/L.
Laboratory investigations: hemoglobin (12.6 g/L), hematocrit (36.4%), leukocytes (12,9 × 109/L), HbA1c (13.5%), fibrinogen (6.8 g/L (normal range 2–4 g/L)), antithrombin III activity (63% (normal range 74%–114%)). Other blood chemistry tests were within normal limits, except for plasma glucose level (12.7 mmol/L). Plasma total testosterone was 1.9 nmol/L (normal range for adult men 12–35 nmol/L). Bacteriological culture: growth of epidermal staphylococcus in the wound. Critical stenosis of popliteal artery and arteria tibialis posterior was found by doppler ultrasound of the legs. Tissue oxygen tension (TpO2) was 28 mm Hg). The patient underwent superficial femoro-peroneal shunting with autovein and marginal resection with disarticulation of toes 2–5 of the left foot. Daily treatment included Cefotaxim 2 g, Metronidazole 600 mg, Fraxiparin 0.6 ml, Thrombo ASS 100 mg, dressing of the wound. The patient also received one injection of testosterone undecanoate 1000 mg, whereupon plasma levels of total testosterone had risen to 38 nmol/L after 14 days.
There is an abundance of studies establishing that men with the metabolic syndrome, cardiovascular disease and type 2 diabetes have lower-than-normal circulating levels of testosterone. But, as yet, there is a paucity of studies on effects of interventions aiming to restore circulating testosterone to normal.
In this pilot study we administered testosterone to men with a diabetic foot who had hypogonadal testosterone levels. There were remarkable improvements.
Testosterone has a stimulatory effect on erythropoiesis occuring within weeks after testosterone administration. In our patients, indeed, a rise of hemoglobin levels was found
There are many studies now establishing a relationship between low serum testosterone and lower extremity peripheral artery disease but results of intervention studies are few. A recent study found a positive effect of administration of testosterone on vascular function though most earlier studies have reported an impaired flow-mediated vasodilatation upon testosterone administration to hypogonadal men. In vitro-studies or animal studies showed that testosterone can exert acute vaso-relaxing effects via non-genomic mechanisms. These effects involve primarily the vascular smooth muscle, without requiring the presence of endothelium, although an endothelial contribution is apparent in some studies. To date, the mechanism behind the vasodilatory action of testosterone is still under debate and might be through either activation of K (+) channels or blockade of Ca (2+) channels in vascular muscle cells.
Apart from effects on the vascular system, testosterone may have had anabolic effects on protein synthesis explaining the beneficial effects of restoring plasma testosterone to the normal range.
In animal experimentation androgens at physiological doses inhibit oxidative-stress-induced platelet aggregation via its receptor, which is associated with the reduction of thromboxane A(2) release from platelets. Testosterone has also been found to have a positive effect on fibrinolysis. In our patients there was a decrease of fibrinogen and an increase of antithrombin activity upon testosterone administration.
Inflammation is increasingly recognized as an etiological factor in cardiovascular disease [21, 22] Testosterone treatment of hypogonadal men shifted the cytokine balance to a state of reduced inflammation. Dihydrotestosterone positively regulated endothelial function through the control of the inflammatory response mediated by nuclear factor-kappaB in endothelial cells. In our study inflammation markers were not studied but there was reduction in leukocyte counts.
The actions of 5alpha-dihydrotestosterone and testosterone were primarily deleterious in cutaneous wound healing in a series of studies. This suggests that administration of testosterone might be unfavorable in this regard.
Our findings are observational and should invite studies with an appropriate design to explore whether normalization of testosterone levels in hypogonadal men with a diabetic foot can improve one of the most incapacitating and potentially lethal complications of diabetes mellitus.
Diabetes mellitus type 2 is very commonly associated with lower-tan-normal serum testosterone levels. In this study three men with a diabetic foot and subnormal serum testosterone, received testosterone treatment. The healing process of the diabetic foot took a favourable turn. This observation invites well-designed studies into the possibly favourable effects of restoring testosterone levels to normal in men suffering from a diabetic foot.
- Svartberg J: Epidemiology: testosterone and the metabolic syndrome. Int J Impot Res. 2007, 19 (2): 124-128. 10.1038/sj.ijir.3901499.View ArticlePubMedGoogle Scholar
- Ding EL, Song Y, Malik VS, Liu S: Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. Jama. 2006, 295 (11): 1288-1299. 10.1001/jama.295.11.1288.View ArticlePubMedGoogle Scholar
- Zitzmann M, Faber S, Nieschlag E: Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006, 91 (11): 4335-4343. 10.1210/jc.2006-0401.View ArticlePubMedGoogle Scholar
- Spark RF: Testosterone, diabetes mellitus, and the metabolic syndrome. Curr Urol Rep. 2007, 8 (6): 467-471. 10.1007/s11934-007-0050-4.View ArticlePubMedGoogle Scholar
- Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, Ouchi Y: Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007, 30 (11): 1029-1034. 10.1291/hypres.30.1029.View ArticlePubMedGoogle Scholar
- Fukui M, Ose H, Kitagawa Y, Yamazaki M, Hasegawa G, Yoshikawa T, Nakamura N: Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus. Metabolism. 2007, 56 (9): 1167-1173. 10.1016/j.metabol.2007.04.011.View ArticlePubMedGoogle Scholar
- Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C: Effects of Two Years of Testosterone Replacement on Insulin Secretion, Insulin Action, Glucose Effectiveness, Hepatic Insulin Clearance and Postprandial Glucose Turnover in Elderly Men. Diabetes care. 2007, 30: 1972-1978. 10.2337/dc07-0359.View ArticlePubMedGoogle Scholar
- Kapoor D, Goodwin E, Channer KS, Jones TH: Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006, 154 (6): 899-906. 10.1530/eje.1.02166.View ArticlePubMedGoogle Scholar
- Boyanov MA, Boneva Z, Christov VG: Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003, 6 (1): 1-7. 10.1080/713604734.View ArticlePubMedGoogle Scholar
- Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S: Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. 2008, 93 (3): 914-919. 10.1210/jc.2007-1692.PubMed CentralView ArticlePubMedGoogle Scholar
- Tivesten A, Mellstrom D, Jutberger H, Fagerberg B, Lernfelt B, Orwoll E, Karlsson MK, Ljunggren O, Ohlsson C: Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. J Am Coll Cardiol. 2007, 50 (11): 1070-1076. 10.1016/j.jacc.2007.04.088.View ArticlePubMedGoogle Scholar
- Webb CM, Elkington AG, Kraidly MM, Keenan N, Pennell DJ, Collins P: Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. Am J Cardiol. 2008, 101 (5): 618-624. 10.1016/j.amjcard.2007.09.114.PubMed CentralView ArticlePubMedGoogle Scholar
- Zitzmann M, Brune M, Nieschlag E: Vascular reactivity in hypogonadal men is reduced by androgen substitution. J Clin Endocrinol Metab. 2002, 87 (11): 5030-5037. 10.1210/jc.2002-020504.View ArticlePubMedGoogle Scholar
- Yildiz O, Seyrek M: Vasodilating mechanisms of testosterone. Exp Clin Endocrinol Diabetes. 2007, 115 (1): 1-6. 10.1055/s-2007-949657.View ArticlePubMedGoogle Scholar
- Traish AM, Goldstein I, Kim NN: Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur urol. 2007, 52 (1): 54-70. 10.1016/j.eururo.2007.02.034.PubMed CentralView ArticlePubMedGoogle Scholar
- Guay A, Jacobson J: The relationship between testosterone levels, the metabolic syndrome (by two criteria), and insulin resistance in a population of men with organic erectile dysfunction. J Sex Med. 2007, 4 (4 Pt 1): 1046-1055. 10.1111/j.1743-6109.2007.00530.x.View ArticlePubMedGoogle Scholar
- Rochira V, Balestrieri A, Madeo B, Granata AR, Carani C: Sildenafil improves sleep-related erections in hypogonadal men: evidence from a randomized, placebo-controlled, crossover study of a synergic role for both testosterone and sildenafil on penile erections. J Androl. 2006, 27 (2): 165-175. 10.2164/jandrol.05077.View ArticlePubMedGoogle Scholar
- Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT: Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab. 2006, 2 (3): 146-159. 10.1038/ncpendmet0120.PubMed CentralView ArticlePubMedGoogle Scholar
- Li S, Li X, Li J, Deng X, Li Y: Inhibition of oxidative-stress-induced platelet aggregation by androgen at physiological levels via its receptor is associated with the reduction of thromboxane A2 release from platelets. Steroids. 2007, 72 (13): 875-880. 10.1016/j.steroids.2007.07.007.View ArticlePubMedGoogle Scholar
- Alexandersen P, Christiansen C: The aging male: testosterone deficiency and testosterone replacement. An up-date. Atherosclerosis. 2004, 173 (2): 157-169. 10.1016/S0021-9150(03)00242-9.View ArticlePubMedGoogle Scholar
- Bhatt DL: Anti-inflammatory agents and antioxidants as a possible "third great wave" in cardiovascular secondary prevention. Am J Cardiol. 2008, 101 (10A): 4D-13D. 10.1016/j.amjcard.2008.02.002.View ArticlePubMedGoogle Scholar
- Hamirani YS, Pandey S, Rivera JJ, Ndumele C, Budoff MJ, Blumenthal RS, Nasir K: Markers of inflammation and coronary artery calcification: A systematic review. Atherosclerosis. 2008, 201: 1-7. 10.1016/j.atherosclerosis.2008.04.045.View ArticlePubMedGoogle Scholar
- Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH: The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004, 89 (7): 3313-3318. 10.1210/jc.2003-031069.View ArticlePubMedGoogle Scholar
- Norata GD, Tibolla G, Seccomandi PM, Poletti A, Catapano AL: Dihydrotestosterone decreases tumor necrosis factor-alpha and lipopolysaccharide-induced inflammatory response in human endothelial cells. J Clin Endocrinol Metab. 2006, 91 (2): 546-554. 10.1210/jc.2005-1664.View ArticlePubMedGoogle Scholar
- Gilliver SC, Ashworth JJ, Ashcroft GS: The hormonal regulation of cutaneous wound healing. Clin Dermatol. 2007, 25 (1): 56-62. 10.1016/j.clindermatol.2006.09.012.View ArticlePubMedGoogle Scholar
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