Editorial
Are low levels of 25(OH) vitamin D and testosterone clinically relevant in men with paraplegia? John E. Morley Divisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, St. Louis, Missouri Keywords: Vitamin D, Testosterone, Paraplegia, Elderly men
The incidence of fractures is twice as common in persons with paraplegia as in the general population (there is limited data on men with tetraplegia). It is related to increased loss of bone mass and altered bone structure and function.1 Deficiency of 25(OH) vitamin D based on serum levels in men with paraplegia ranges between 32% to 73.5%.1–3 A small subset of these men have elevated parathormone (PTH) levels, which the Institute of Medicine has used as a biomarker of 25(OH)D deficiency. Elevations in PTH result in calcium being drawn off bone resulting in accelerated osteopenia. While there are numerous other putative effects of vitamin D, at present the evidence suggests that the major role of vitamin D is to maintain calcium homeostasis and bone integrity.4 In recent times the measurement of 25(OH) D levels has become problematic. This is because there are marked ethnic differences in the level of the binding protein for vitamin D.5 Persons with dark skin have very low levels of vitamin D binding protein, and therefore lower levels of 25(OH) D.6 A longitudinal study has shown that with aging 25(OH) D levels decline, due to decreased skin synthesis of cholecalciferol, decreased vitamin D absorption from the gut and decreased sun exposure.7 Thus, in younger persons with paraplegia 25(OH) D levels should be measured with PTH to determine whether the low level is having a biological effect. In persons over 50 years of age, it is reasonable to give 1000 IU of vitamin D daily, without measurement of 25(OH) D. Higher doses should be avoided as there is emerging evidence that higher levels of calcium, even within the normal range, may result in memory loss and cardiovascular disease.8,9 Correspondence to: John E. Morley, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, USA. Email: [email protected].
© The Academy of Spinal Cord Injury Professionals, Inc. 2016 DOI 10.1080/10790268.2016.1172413
The role of testosterone in persons with paraplegia is more complex. The original studies in the 1970s showed that a small percentage of young males with paraplegia have low testosterone, a larger group have seminiferous tubule abnormalities and that there are minor alterations in gonatrophin dynamics.10–12 In 2014, Bauman et al. 2 examined both old and young males with paraplegia and found that in those over 50 years of age more than 50% had low testosterone levels compared to 15% aged 30 to 39 years. His data suggested that paraplegia results in an accelerated rate of decline in testosterone levels associated with an increase in sex hormone binding globulin and, therefore, an even greater decrease in free testosterone. In a controlled study, testosterone given for 12 months was shown to increase lean body mass.13 A case report suggested “substantial” improvement in muscle function when the patient received testosterone pellets for 6 months after a rock climbing accident.14 Besides the effects of testosterone on muscle mass and strength, it also decreases fat mass and enhances bone mineral density in persons who are hypogonadal.15 In younger persons hypogonadism is associated with cardiovascular disease, but in older persons testosterone replacement may increase myocardial infarction.16,17 Barbonetti et al.18 found that low testosterone was independently associated with non-alcoholic fatty liver disease in men with paraplegia. Testosterone increases hematocrit. It may aggravate sleep apnea. The long term treatment of testosterone in young people on prostate disease is unknown. Low levels of testosterone and 25(OH) vitamin D are seen in persons with poor health. This seems the most likely reason for the correlation seen by Barbonetti et al.1 This is particularly likely as another study in
The Journal of Spinal Cord Medicine
2016
VOL.
39
NO.
3
253
Morley
Are low levels of 25(OH) vitamin D and testosterone clinically relevant in men with paraplegia?
males with paraplegia failed to find a correlation.19 In addition, both 25(OH) vitamin D and testosterone decline with age.7,20 Vitamin D has been showed to increase steroidogenesis in testicular cell cultures.21 In human replacement studies vitamin D replacement increased testosterone in 1 out of 3 studies.22–24 Overall, it would appear that the direct effect of vitamin D on testosterone is not statistically significant. In conclusion, 25(OH) vitamin D deficiency and hypogonadism may both produce clinically significant deleterious effects on males with paraplegia. Vitamin D replacement at 1000 IU daily appears warranted in most males with paraplegia over 50 years of age and in a smaller subset of younger men with paraplegia. There would appear to be an advantage of testosterone replacement, at least in younger males. Because of the potential side effects of testosterone, a large controlled trial of testosterone replacement in males with paraplegia and hypogonadism should be undertaken.
Disclaimer statements
8
9 10 11 12 13
14 15 16 17
Contributors None. Funding None. Conflicts of interest None.
18
Ethics approval None.
References
19
1 Hummel K, Craven BC, Giangregorio L. Serum 25(OH)D, PTH and correlates of suboptimal 25(OH)D levels in persons with chronic spinal cord injury. Spinal Cord 2012;50(11):812–6. 2 Barbonetti A, Vassallo MR, Felzani G, Francavilla S, Francavilla F. Association between 25(OH)-vitamin D and testosterone levels: Evidence from men with chronic spinal cord injury. J Spinal Cord Med 2016;39(3). 3 Bauman WA, La Fountaine MF, Spungen AM. Age-related prevalence of low testosterone in men with spinal cord injury. J Spinal Cord Med 2014;37(1):32–9. 4 Morley JE. Vitamin D redux. J Am Med Dir Assoc 2009;10(9): 591–2. 5 Yousefzadeh P, Shapses SA, Wang X. Vitamin D binding protein impact on 25-hydroxyvitamin D levels under different physiologic and pathologic conditions. Int J Endocrinol 2014;2014;981581. Doi: 10.1155/2014/0981561. Epub 2014, April 28. 6 Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369(21): 1991–2000. 7 Perry HM 3rd, Horowitz M, Morley JE, Patrick P, Vellas P, Baumgartner R, Garry PJ. Longitudinal changes in serum 25-
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The Journal of Spinal Cord Medicine
2016
VOL.
39
NO.
3
20
21
22 23
24
hydroxyvitamin D in older people. Metabolism 1999;48(8): 1028–32. Michaëlsson K, Melhus H, Warensjö Lemming E, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: Community based prospective longitudinal cohort study. BMJ 2013;Feb 12; 346:f228. Morley JE. Dementia: Does vitamin D modulate cognition? Nat Rev Neurol 2014;10(11):613–4. Mizutani S, Sonoda T, Matsumoto K, Iwasa K. Plasma testosterone concentration in paraplegic men. J Endocrinol 1972;54(2): 363–4. Hayes PJ, Krishnan KR, Diver MJ, Hipkin LJ, Davis JC. Testicular endocrine function in paraplegic men. Clin Endocrinol (Oxf) 1979;11(5):549–52. Morley JE, Distiller LA, Lissoos I, Lipschitz R, Kay G, Searle DL, et al. Testicular function in patients with spinal cord damage. Horm Metab Res 1979;11(12):679–82. Bauman WA, Cirnigliaro CM, La Fountaine MF, Jensen AM, Wecht JM, Kirshblum SC, et al. A small-scale clinical trial to determine the safety and efficacy of testosterone replacement therapy in hypogonadal men with spinal cord injury. Horm Metab Res 2011;43(8):574–9. Gray KM, Derosa A. Subcutaneous pellet testosterone replacement therapy: The “first steps” in treating men with spinal cord injuries. J Am Osteopath Assoc 2013;113(12):921–5. Kim MJ, Morley JE. The hormonal fountains of youth: Myth or reality? J Endocrinol Invest 2005;28(11 Suppl Proceedings):5–14. Chahla EJ, Hayek ME, Morley JE. Testosterone replacement therapy and cardiovascular risk factors modification. Aging Male 2011;14(2):83–90. Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk. Endocr Pract 2015;21(9):1066–73. Barbonetti A, Caterina Vassallo MR, Cotugno M, Felzani G, Grancavilla S, Francavilla F. Low testosterone and non-alcoholic fatty liver disease: Evidence for their independent association in men with chronic spinal cord injury. J Spinal Cord Med 2015; Jan 23 (Epub ahead of print]. Gaspar AP, Brandão CM, Lazaretti-Castro M. Bone mass and hormone analysis in patients with spinal cord injury: Evidence for a gonadal axis disruption. J Clin Endocrinol Metab 2014; 99(12):4649–55. Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Morley PM, Stauber PM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46(4):410–3. Zanatta L, Zamoner A, Zanatta AP, Bouraïma-Lelong H, Delalande C, Bois C, et al. Nongenomic and genomic effects of 1a,25(OH)2 vitamin D3 in rat testis. Life Sci 2011;89(15–16): 515–23. Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res 2011;43(3):223–5. Jorde R, Grimnes G, Hutchinson MS, Kjaergaard M, Kamycheva E, Svartberg J. Supplementation with vitamin D does not increase serum testosterone levels in healthy males. Horm Metab Res 2013; 45(9):675–81. Heijboer AC, Ooseterwerff M, Schroten NF, Eekhoff EM, Chel VG, de Boer RA, et al. Vitamin D supplementation and testosterone concentrations in male human subjects. Clin Endocrinol (Oxf ) 2015;83(1):105–10.
Are low levels of 25(OH) vitamin D and testosterone clinically relevant in men with paraplegia? John E. Morley Divisions of Geriatric Medicine and Endocrinology, Saint Louis University School of Medicine, St. Louis, Missouri Keywords: Vitamin D, Testosterone, Paraplegia, Elderly men
The incidence of fractures is twice as common in persons with paraplegia as in the general population (there is limited data on men with tetraplegia). It is related to increased loss of bone mass and altered bone structure and function.1 Deficiency of 25(OH) vitamin D based on serum levels in men with paraplegia ranges between 32% to 73.5%.1–3 A small subset of these men have elevated parathormone (PTH) levels, which the Institute of Medicine has used as a biomarker of 25(OH)D deficiency. Elevations in PTH result in calcium being drawn off bone resulting in accelerated osteopenia. While there are numerous other putative effects of vitamin D, at present the evidence suggests that the major role of vitamin D is to maintain calcium homeostasis and bone integrity.4 In recent times the measurement of 25(OH) D levels has become problematic. This is because there are marked ethnic differences in the level of the binding protein for vitamin D.5 Persons with dark skin have very low levels of vitamin D binding protein, and therefore lower levels of 25(OH) D.6 A longitudinal study has shown that with aging 25(OH) D levels decline, due to decreased skin synthesis of cholecalciferol, decreased vitamin D absorption from the gut and decreased sun exposure.7 Thus, in younger persons with paraplegia 25(OH) D levels should be measured with PTH to determine whether the low level is having a biological effect. In persons over 50 years of age, it is reasonable to give 1000 IU of vitamin D daily, without measurement of 25(OH) D. Higher doses should be avoided as there is emerging evidence that higher levels of calcium, even within the normal range, may result in memory loss and cardiovascular disease.8,9 Correspondence to: John E. Morley, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, USA. Email: [email protected].
© The Academy of Spinal Cord Injury Professionals, Inc. 2016 DOI 10.1080/10790268.2016.1172413
The role of testosterone in persons with paraplegia is more complex. The original studies in the 1970s showed that a small percentage of young males with paraplegia have low testosterone, a larger group have seminiferous tubule abnormalities and that there are minor alterations in gonatrophin dynamics.10–12 In 2014, Bauman et al. 2 examined both old and young males with paraplegia and found that in those over 50 years of age more than 50% had low testosterone levels compared to 15% aged 30 to 39 years. His data suggested that paraplegia results in an accelerated rate of decline in testosterone levels associated with an increase in sex hormone binding globulin and, therefore, an even greater decrease in free testosterone. In a controlled study, testosterone given for 12 months was shown to increase lean body mass.13 A case report suggested “substantial” improvement in muscle function when the patient received testosterone pellets for 6 months after a rock climbing accident.14 Besides the effects of testosterone on muscle mass and strength, it also decreases fat mass and enhances bone mineral density in persons who are hypogonadal.15 In younger persons hypogonadism is associated with cardiovascular disease, but in older persons testosterone replacement may increase myocardial infarction.16,17 Barbonetti et al.18 found that low testosterone was independently associated with non-alcoholic fatty liver disease in men with paraplegia. Testosterone increases hematocrit. It may aggravate sleep apnea. The long term treatment of testosterone in young people on prostate disease is unknown. Low levels of testosterone and 25(OH) vitamin D are seen in persons with poor health. This seems the most likely reason for the correlation seen by Barbonetti et al.1 This is particularly likely as another study in
The Journal of Spinal Cord Medicine
2016
VOL.
39
NO.
3
253
Morley
Are low levels of 25(OH) vitamin D and testosterone clinically relevant in men with paraplegia?
males with paraplegia failed to find a correlation.19 In addition, both 25(OH) vitamin D and testosterone decline with age.7,20 Vitamin D has been showed to increase steroidogenesis in testicular cell cultures.21 In human replacement studies vitamin D replacement increased testosterone in 1 out of 3 studies.22–24 Overall, it would appear that the direct effect of vitamin D on testosterone is not statistically significant. In conclusion, 25(OH) vitamin D deficiency and hypogonadism may both produce clinically significant deleterious effects on males with paraplegia. Vitamin D replacement at 1000 IU daily appears warranted in most males with paraplegia over 50 years of age and in a smaller subset of younger men with paraplegia. There would appear to be an advantage of testosterone replacement, at least in younger males. Because of the potential side effects of testosterone, a large controlled trial of testosterone replacement in males with paraplegia and hypogonadism should be undertaken.
Disclaimer statements
8
9 10 11 12 13
14 15 16 17
Contributors None. Funding None. Conflicts of interest None.
18
Ethics approval None.
References
19
1 Hummel K, Craven BC, Giangregorio L. Serum 25(OH)D, PTH and correlates of suboptimal 25(OH)D levels in persons with chronic spinal cord injury. Spinal Cord 2012;50(11):812–6. 2 Barbonetti A, Vassallo MR, Felzani G, Francavilla S, Francavilla F. Association between 25(OH)-vitamin D and testosterone levels: Evidence from men with chronic spinal cord injury. J Spinal Cord Med 2016;39(3). 3 Bauman WA, La Fountaine MF, Spungen AM. Age-related prevalence of low testosterone in men with spinal cord injury. J Spinal Cord Med 2014;37(1):32–9. 4 Morley JE. Vitamin D redux. J Am Med Dir Assoc 2009;10(9): 591–2. 5 Yousefzadeh P, Shapses SA, Wang X. Vitamin D binding protein impact on 25-hydroxyvitamin D levels under different physiologic and pathologic conditions. Int J Endocrinol 2014;2014;981581. Doi: 10.1155/2014/0981561. Epub 2014, April 28. 6 Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369(21): 1991–2000. 7 Perry HM 3rd, Horowitz M, Morley JE, Patrick P, Vellas P, Baumgartner R, Garry PJ. Longitudinal changes in serum 25-
254
The Journal of Spinal Cord Medicine
2016
VOL.
39
NO.
3
20
21
22 23
24
hydroxyvitamin D in older people. Metabolism 1999;48(8): 1028–32. Michaëlsson K, Melhus H, Warensjö Lemming E, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: Community based prospective longitudinal cohort study. BMJ 2013;Feb 12; 346:f228. Morley JE. Dementia: Does vitamin D modulate cognition? Nat Rev Neurol 2014;10(11):613–4. Mizutani S, Sonoda T, Matsumoto K, Iwasa K. Plasma testosterone concentration in paraplegic men. J Endocrinol 1972;54(2): 363–4. Hayes PJ, Krishnan KR, Diver MJ, Hipkin LJ, Davis JC. Testicular endocrine function in paraplegic men. Clin Endocrinol (Oxf) 1979;11(5):549–52. Morley JE, Distiller LA, Lissoos I, Lipschitz R, Kay G, Searle DL, et al. Testicular function in patients with spinal cord damage. Horm Metab Res 1979;11(12):679–82. Bauman WA, Cirnigliaro CM, La Fountaine MF, Jensen AM, Wecht JM, Kirshblum SC, et al. A small-scale clinical trial to determine the safety and efficacy of testosterone replacement therapy in hypogonadal men with spinal cord injury. Horm Metab Res 2011;43(8):574–9. Gray KM, Derosa A. Subcutaneous pellet testosterone replacement therapy: The “first steps” in treating men with spinal cord injuries. J Am Osteopath Assoc 2013;113(12):921–5. Kim MJ, Morley JE. The hormonal fountains of youth: Myth or reality? J Endocrinol Invest 2005;28(11 Suppl Proceedings):5–14. Chahla EJ, Hayek ME, Morley JE. Testosterone replacement therapy and cardiovascular risk factors modification. Aging Male 2011;14(2):83–90. Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk. Endocr Pract 2015;21(9):1066–73. Barbonetti A, Caterina Vassallo MR, Cotugno M, Felzani G, Grancavilla S, Francavilla F. Low testosterone and non-alcoholic fatty liver disease: Evidence for their independent association in men with chronic spinal cord injury. J Spinal Cord Med 2015; Jan 23 (Epub ahead of print]. Gaspar AP, Brandão CM, Lazaretti-Castro M. Bone mass and hormone analysis in patients with spinal cord injury: Evidence for a gonadal axis disruption. J Clin Endocrinol Metab 2014; 99(12):4649–55. Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Morley PM, Stauber PM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46(4):410–3. Zanatta L, Zamoner A, Zanatta AP, Bouraïma-Lelong H, Delalande C, Bois C, et al. Nongenomic and genomic effects of 1a,25(OH)2 vitamin D3 in rat testis. Life Sci 2011;89(15–16): 515–23. Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res 2011;43(3):223–5. Jorde R, Grimnes G, Hutchinson MS, Kjaergaard M, Kamycheva E, Svartberg J. Supplementation with vitamin D does not increase serum testosterone levels in healthy males. Horm Metab Res 2013; 45(9):675–81. Heijboer AC, Ooseterwerff M, Schroten NF, Eekhoff EM, Chel VG, de Boer RA, et al. Vitamin D supplementation and testosterone concentrations in male human subjects. Clin Endocrinol (Oxf ) 2015;83(1):105–10.
