Restricted accessResearch articleFirst published online 2020-05-21
Testosterone replacement in hypogonadal men during inpatient rehabilitation following traumatic brain injury: Results from a double-blind,placebo-controlled clinical pilot study
Endocrinopathy, including hypogonadism, is common following traumatic brain injury (TBI). Prior evidence suggests hypogonadism is associated with poorer function.
OBJECTIVE:
Determine the feasibility, safety, and efficacy of testosterone (T) therapy in hypogonadal men following TBI in acute rehabilitation.
DESIGN:
Randomized, double blind, placebo-controlled pilot trial.
SETTING:
Inpatient rehabilitation brain injury unit.
PARTICIPANTS:
Men ages 18 –65, post moderate to severe TBI receiving inpatient rehabilitation.
INTERVENTIONS:
Transdermal T gel or placebo.
MAIN OUTCOME MEASURES:
Revised FIM™ score, strength, adverse events.
RESULTS:
Of 498 screened, 70 participants were enrolled, and 22 meeting all criteria were randomized into placebo (n = 10) or physiologic T therapy (n = 12). There was no significant difference between groups in rate of improvement on the FIM™ (intercepts t = –0.31, p = 0.7593, or slopes t = 0.61, p = 0.5472). The Treatment group demonstrated the greatest absolute improvement in FIM™ scores and grip strength compared to Placebo or Normal T groups. There was no difference in adverse events between groups. Percentage of time with agitation or aggression was highest in the Placebo group.
CONCLUSIONS:
Although there were no significant differences in rates of recovery, treatment group subjects showed greater absolute functional and strength improvement compared to the Placebo or Normal T groups.
Agha,A., Phillips,J., O’Kelly,P., Tormey,W., & Thompson,C. J. (2005). The natural history of post-traumatic hypopituitarism: implications for assessment and treatment, Am J Med, 118(12), 1416.
2.
Bavisetty,S., McArthur,D. L., Dusick,J. R., Wang,C., Cohan,P., Boscardin,W. J.,. . . Kelly,D. F. (2008). Chronic hypopituitarism after traumatic brain injury: risk assessment and relationship to outcome, Neurosurgery, 62(5), 1093–1084;discussion 1093-1084.
3.
Beauchet,O. (2006). Testosterone and cognitive function: current clinical evidence of a relationship, Eur J Endocrinol, 155(6), 773–781.
4.
Behan,L. A., Phillips,J., Thompson,C. J., & Agha,A. (2008). Neuroendocrine disorders after traumatic brain injury, J Neurol Neurosurg Psychiatry, 79(7), 753–759.
5.
Cantor,J. B., Ashman,T., Gordon,W., Ginsberg,A., Engmann,C., Egan,M.,. . . Flanagan,S. (2008). Fatigue after traumatic brain injury and its impact on participation and quality of life, J Head Trauma Rehabil, 23(1), 41–51. doi: 10.1097/01.HTR.0000308720.70288.af
6.
Carlson,N. E., Brenner,L. A., Wierman,M. E., Harrison-Felix,C., Morey,C., Gallagher,S., & Ripley,D. (2009). Hypogonadism on admission to acute rehabilitation is correlated with lower functional status at admission and discharge, Brain Inj, 23(4), 336–344. doi: 909972518 [pii] 10.1080/02699050902788535
7.
Cherrier,M. M., Craft,S., & Matsumoto,A. H. (2003). Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report, J Androl, 24(4), 568–576.
Dodds,T. A., Martin,D. P., Stolov,W. C., & Deyo,R. A. (1993). A validation of the functional independence measurement and its performance among rehabilitation inpatients, Arch Phys Med Rehabil, 74(5), 531–536. doi: 0003-9993(93)90119-U [pii]
10.
FitzmauriceG., L.N., WareJ. (2011). Applied Longitudinal Analysis, Second Edition. Hoboken NJ: John Wiley & Sons, Inc.
11.
Folstein,M. F., Folstein,S. E., & McHugh,P. R. (1975). Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician, J Psychiatr Res, 12(3), 189–198.
12.
Gibney,J., Wolthers,T., Johannsson,G., Umpleby,A. M., & Ho,K. K. (2005). Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men, Am J Physiol Endocrinol Metab, 289(2), E266–271.
13.
Granger,C. V., Cotter,A. C., Hamilton,B. B., Fiedler,R. C., & Hens,M. M. (1990). Functional assessment scales: a study of persons with multiple sclerosis, Arch Phys Med Rehabil, 71(11), 870–875.
14.
Granger,C. V., Divan,N., & Fiedler,R. C. (1995). Functional assessment scales. A study of persons after traumatic brain injury, Am J Phys Med Rehabil, 74(2), 107–113.
15.
Granger,C. V., Hamilton,B. B., Linacre,J. M., Heinemann,A. W., & Wright,B. D. (1993). Performance profiles of the functional independence measure, Am J Phys Med Rehabil, 72(2), 84–89.
16.
Hamilton,B. B., Laughlin,J. A., Granger,C. V., & Kayton,R. M. (1991). Interrater agreement of the seven-level Functional Independance Measure (FIM, Archives of Physical Medicine and Rehabilitation, 72, 790.
17.
Hart,T., Millis,S., Novack,T., Englander,J., Fidler-Sheppard,R., & Bell,K. R. (2003). The relationship between neuropsychologic function and level of caregiver supervision at 1 year after traumatic brain injury, Arch Phys Med Rehabil, 84(2), 221–230. doi: 10.1053/apmr.2003.50023
18.
Hassett,L. M., Moseley,A. M., Tate,R., & Harmer,A. R. (2008). Fitness training for cardiorespiratory conditioning after traumatic brain injury. Cochrane Database Syst Rev(2), CD006123. doi:10.1002/14651858.CD006123.pub2
19.
Heinemann,A. W., Kirk,P., Hastie,B. A., Semik,P., Hamilton,B. B., Linacre,J. M.,. . . Granger,C. (1997). Relationships between disability measures and nursing effort during medical rehabilitation for patients with traumatic brain and spinal cord injury, Arch Phys Med Rehabil, 78(2), 143–149. doi: S0003-9993(97)90255-0 [pii]
20.
Heinemann,A. W., Linacre,J. M., Wright,B. D., Hamilton,B. B., & Granger,C. (1993). Relationships between impairment and physical disability as measured by the functional independence measure, Arch Phys Med Rehabil, 74(6), 566–573. doi: 0003-9993(93)90153-2 [pii]
21.
Janowsky,J. S., Oviatt,S. K., & Orwoll,E. S. (1994). Testosterone influences spatial cognition in older men, Behav Neurosci, 108(2), 325–332.
22.
Kelly,D. F., Gonzalo,I. T., Cohan,P., Berman,N., Swerdloff,R., & Wang,C. (2000). Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report, J Neurosurg, 93(5), 743–752.
23.
Kido,Y., Sakazume,S., Abe,Y., Oto,Y., Itabashi,H., Shiraishi,M.,. . . Nagai,T. (2013). Testosterone replacement therapy to improve secondary sexual characteristics and body composition without adverse behavioral problems in adult male patients with Prader-Willi syndrome: an observational study, Am J Med Genet A, 161a(9), 2167–2173. doi: 10.1002/ajmg.a.36048
24.
Krakau,K., Hansson,A., Karlsson,T., de Boussard,C. N., Tengvar,C., & Borg,J. (2007). Nutritional treatment of patients with severe traumatic brain injury during the first six months after injury, Nutrition, 23(4), 308–317. doi: S0899-9007(07)00018-4 [pii] 10.1016/j.nut.2007.01.010
25.
Levin,H. S., O’Donnell,V. M., & Grossman,R. G. (1979). The Galveston Orientation and Amnesia Test. A practical scale to assess cognition after head injury, J Nerv Ment Dis, 167(11), 675–684.
26.
Linacre,J. M., Heinemann,A. W., Wright,B. D., Granger,C. V., & Hamilton,B. B. (1994). The structure and stability of the Functional Independence Measure, Arch Phys Med Rehabil, 75(2), 127–132. doi: 0003-9993(94)90384-0 [pii]
27.
Mehta,N. M., Bechard,L. J., Leavitt,K., & Duggan,C. (2008). Severe weight loss and hypermetabolic paroxysmal dysautonomia following hypoxic ischemic brain injury: the role of indirect calorimetry in the intensive care unit, JPEN J Parenter Enteral Nutr, 32(3), 281–284. doi: 32/3/281 [pii] 10.1177/0148607108316196
28.
Molenberghs,G. a. K., M. (2007). Missing Data in Clinical Studies.. West Sussex P019 8SQ, England: John Wiley & Sons, Ltd.
29.
Nichol,A. D., Higgins,A. M., Gabbe,B. J., Murray,L. J., Cooper,D. J., & Cameron,P. A. (2011). Measuring functional and quality of life outcomes following major head injury: common scales and checklists, Injury, 42(3), 281–287. doi: 10.1016/j.injury.2010.11.047
30.
O’Connor,D. B., Archer,J., Hair,W. M., & Wu,F. C. (2002). Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men, Physiol Behav, 75(4), 557–566.
31.
Page,S. T., Amory,J. K., Bowman,F. D., Anawalt,B. D., Matsumoto,A. M., Bremner,W. J., & Tenover,J. L. (2005). Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T, J Clin Endocrinol Metab, 90(3), 1502–1510.
32.
Powner,D. J., Boccalandro,C., Alp,M. S., & Vollmer,D. G. (2006). Endocrine failure after traumatic brain injury in adults, Neurocrit Care, 5(1), 61–70.
33.
Rosner,W., Auchus,R. J., Azziz,R., Sluss,P. M., & Raff,H. (2007). Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement, J Clin Endocrinol Metab, 92(2), 405–413.
34.
Schneider,H. J., Kreitschmann-Andermahr,I., Ghigo,E., Stalla,G. K., & Agha,A. (2007). Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, Jama, 298(12), 1429–1438.
35.
Sourial,N., & Fenton,F. (1988). Testosterone treatment of an XXYY male presenting with aggression: a case report, Can J Psychiatry, 33(9), 846–850.
36.
Storer,T. W., Magliano,L., Woodhouse,L., Lee,M. L., Dzekov,C., Dzekov,J.,. . . Bhasin,S. (2003). Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension, J Clin Endocrinol Metab, 88(4), 1478–1485.
37.
Traumatic Brain Injury Model Systems National Data Center. (2007). Traumatic Brain Injury Model Systems National Database. Retrieved from Englewood:
38.
Woolf,P. D., Hamill,R. W., McDonald,J. V., Lee,L. A., & Kelly,M. (1985). Transient hypogonadotropic hypogonadism caused by critical illness, J Clin Endocrinol Metab, 60(3), 444–450.
39.
Yaffe,K., Lui,L. Y., Zmuda,J., & Cauley,J. (2002). Sex hormones and cognitive function in older men, J Am Geriatr Soc, 50(4), 707–712.
40.
Zitzmann,M. (2006). Testosterone and the brain, Aging Male, 9(4), 195–199. doi: 10.1080/13685530601040679
