Physiological and Psychological Effects of Testosterone During Severe Energy Deficit and Recovery

Exercise Clinical Trial

— OPS  

Official title:

Physiological and Psychological Effects of Testosterone During Severe Energy Deficit and Recovery: a Randomized, Placebo Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02734238
• Other study ID #: PBRC 2015-063
• Status: Completed
• Phase: Phase 4
• Start date: April 2016
• Est. completion date: December 2017

Study information

• Verified date: January 2019
• Source: Pennington Biomedical Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this study is to determine whether maintaining a eugonadal state, during severe, sustained energy deficit, attenuates physiological decrements, particularly the loss of lean body mass.

Description:

This study will enroll up to 60 physically active men in a 3-phase randomized, placebo-controlled trial. After completing a 14-day (free-living, phase 1), energy-adequate, diet-acclimation phase (protein, 1.6 g∙kg-1∙d-1; fat 30% total energy intake, with remaining energy derived from carbohydrate), participants will be randomized to one of two experimental groups and undergo a 28-day (live-in, phase 2), 55% energy deficit phase: energy deficit alone (DEF) or energy deficit + exogenous testosterone (DEF+TEST). Recovery (free-living, phase 3) will be assessed after completing phase 2 to determine when body mass has been recovered within ± 2.5% of initial body mass (duration will vary, 42-day maximum for phase 3). This study will delineate the contribution of testosterone declines from the physical and mental demands encountered by Warfighters during military training and combat operations on complex markers of physiological and psychological status, addressing a direct, consistently observed, gap in knowledge.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 39 Years

Eligibility

Inclusion Criteria:

• Physically active (at least 2 days per week aerobic and/or resistance exercise)

• Not taking any prescription medications and/or willing to refrain from all medication use prior to and throughout the entire study period, unless provided/approved by the study physician

• Willing to refrain from alcohol, smoking, e-cigarettes, or use of any nicotine product, caffeine, and dietary supplement use throughout the entire study period

• At the discretion of the study physician, wash-out period for medications, supplements, and over-the-counter medications is = 1 to 4 weeks

• Wash-out period for caffeine and alcohol is = 7 days

• Willing to live on the Pennington Biomedical Research Center inpatient unit for 28 consecutive days

• Willing to have a urine drug screening

• Meets age-specific U.S. Army body composition standards according to Army Regulation 600-9, which includes estimates of percent body fat based on height, weight, and circumference measures (neck and waist)

• Total testosterone concentration is within the normal physiological range, total testosterone (300-1,000 ng/dL).

Exclusion Criteria:

• Musculoskeletal injuries that compromise exercise capability

• Diagnosed cardiometabolic disorders (i.e., hypertension, hyperlipidemia, kidney disease, diabetes, etc.)

• Allergies or intolerance to foods, vegetarian practices, or history of complications with lidocaine

• Anabolic steroid, human growth hormone, or nutritional testosterone precursor-like supplement use within the past 6 months

• Will not refrain from smoking (any nicotine product), alcohol, caffeine, or any other dietary supplement during the study

• Any use of antibiotics, except topical antibiotics, within 3 months of study participation

• Colonoscopy within 3 months of study participation

• Chronic use of laxatives, stool softeners, antacids, or anti-diarrheal medications (= once a week)

• History of gastrointestinal disease (e.g., celiac, irritable bowel syndrome, colitis, Crohn's disease)

• Restrained eater (the Three-Factor Eating Questionnaire) as assessed by the study's psychological and behavioral assessment staff

• Adults unable to consent

• Women

• Prisoners

• Metal implants, claustrophobia, head size incompatible with MRI equipment, etc.

• Sedentary or engages in <2 days of physical activity per week (aerobic and/or resistance training)

• Exceeds age-specific U.S. Army body composition standards according to Army Regulation 600-9

• Previous history of kidney stones unless otherwise approved by the medical investigator

• Systolic blood pressure > 150 or diastolic blood pressure > 95 mmHg

• Previous history of breast or prostate cancer

• Previous history of Chronic Obstructive Pulmonary Disease or Obstructive Sleep Apnea

• Findings of lab results of prostate-specific antigen > 3ng/ml, Hematocrit > 50%, or positive urine drug screening

• Based on the investigative team's clinical judgment, a subject may not be appropriate for participation in the study

Related Conditions & MeSH terms

• Caloric Restriction
• Exercise

Intervention

Drug:
• Sesame Oil
200 mg sesame oil by intramuscular injection weekly on days 15, 21, 28, and 35
• testosterone enanthate
200 mg testosterone enanthate by intramuscular injection weekly on days 15, 21, 28, and 35

Locations

Country	Name	City	State
United States	Pennington Biomedical Research Center	Baton Rouge	Louisiana

Sponsors (5)

Lead Sponsor	Collaborator
Pennington Biomedical Research Center	Defence Research and Development Canada, MyoSyntax, United States Army Research Institute of Environmental Medicine, United States Department of Defense

Country where clinical trial is conducted

United States, 

References & Publications (132)

Alemany JA, Nindl BC, Kellogg MD, Tharion WJ, Young AJ, Montain SJ. Effects of dietary protein content on IGF-I, testosterone, and body composition during 8 days of severe energy deficit and arduous physical activity. J Appl Physiol (1985). 2008 Jul;105(1):58-64. doi: 10.1152/japplphysiol.00005.2008. Epub 2008 May 1. — View Citation

Anderson RA, Martin CW, Kung AW, Everington D, Pun TC, Tan KC, Bancroft J, Sundaram K, Moo-Young AJ, Baird DT. 7Alpha-methyl-19-nortestosterone maintains sexual behavior and mood in hypogonadal men. J Clin Endocrinol Metab. 1999 Oct;84(10):3556-62. — View Citation

Apicella CL, Dreber A, Mollerstrom J. Salivary testosterone change following monetary wins and losses predicts future financial risk-taking. Psychoneuroendocrinology. 2014 Jan;39:58-64. doi: 10.1016/j.psyneuen.2013.09.025. Epub 2013 Oct 6. — View Citation

Areta JL, Burke LM, Camera DM, West DW, Crawshay S, Moore DR, Stellingwerff T, Phillips SM, Hawley JA, Coffey VG. Reduced resting skeletal muscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit. Am J Physiol Endocrinol Metab. 2014 Apr 15;306(8):E989-97. doi: 10.1152/ajpendo.00590.2013. Epub 2014 Mar 4. — View Citation

Asarian L, Geary N. Sex differences in the physiology of eating. Am J Physiol Regul Integr Comp Physiol. 2013 Dec;305(11):R1215-67. doi: 10.1152/ajpregu.00446.2012. Epub 2013 Jul 31. Review. — View Citation

Baddeley AD. A 3 min reasoning test based on grammatical transformation. Psychon Sci. 1968;10(10):341-342.

Baker LA, Pearcey SM, Dabbs JM Jr. Testosterone, alcohol, and civil and rough conflict resolution strategies in lesbian couples. J Homosex. 2002;42(4):77-88. — View Citation

Banderet LE, Lieberman HR. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull. 1989 Apr;22(4):759-62. — View Citation

Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I. The "Reading the Mind in the Eyes" Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001 Feb;42(2):241-51. — View Citation

Bartels M, Van den Berg M, Sluyter F, Boomsma DI, de Geus EJ. Heritability of cortisol levels: review and simultaneous analysis of twin studies. Psychoneuroendocrinology. 2003 Feb;28(2):121-37. Review. — View Citation

Baumgart DC, Dignass AU. Intestinal barrier function. Curr Opin Clin Nutr Metab Care. 2002 Nov;5(6):685-94. Review. — View Citation

Beauchet O. Testosterone and cognitive function: current clinical evidence of a relationship. Eur J Endocrinol. 2006 Dec;155(6):773-81. Review. — View Citation

Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha-Hikim I, Shen R, Storer TW. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1172-81. — View Citation

Blundell J, de Graaf C, Hulshof T, Jebb S, Livingstone B, Lluch A, Mela D, Salah S, Schuring E, van der Knaap H, Westerterp M. Appetite control: methodological aspects of the evaluation of foods. Obes Rev. 2010 Mar;11(3):251-70. doi: 10.1111/j.1467-789X.2010.00714.x. Epub 2010 Jan 29. Review. — View Citation

Braniste V, Leveque M, Buisson-Brenac C, Bueno L, Fioramonti J, Houdeau E. Oestradiol decreases colonic permeability through oestrogen receptor beta-mediated up-regulation of occludin and junctional adhesion molecule-A in epithelial cells. J Physiol. 2009 Jul 1;587(Pt 13):3317-28. doi: 10.1113/jphysiol.2009.169300. Epub 2009 May 11. — View Citation

Bray GA, Redman LM, de Jonge L, Covington J, Rood J, Brock C, Mancuso S, Martin CK, Smith SR. Effect of protein overfeeding on energy expenditure measured in a metabolic chamber. Am J Clin Nutr. 2015 Mar;101(3):496-505. doi: 10.3945/ajcn.114.091769. Epub 2015 Jan 14. — View Citation

Burnham TC. High-testosterone men reject low ultimatum game offers. Proc Biol Sci. 2007 Sep 22;274(1623):2327-30. — View Citation

Bush G, Shin LM. The Multi-Source Interference Task: an fMRI task that reliably activates the cingulo-frontal-parietal cognitive/attention network. Nat Protoc. 2006;1(1):308-13. — View Citation

Buss AH, Perry M. The aggression questionnaire. J Pers Soc Psychol. 1992 Sep;63(3):452-9. — View Citation

Butcher J, Graham J, Tellegen A, Dahlstrom W, Kaemmer B. Minnesota Multiphasic Personality Inventory-2 (MMPI-2): Manual for administration, scoring, and interpretation 2nd ed. Minneapolis, MN: University of Minnesota Press; 2001.

Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Peña AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010 May;7(5):335-6. doi: 10.1038/nmeth.f.303. Epub 2010 Apr 11. — View Citation

Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, Gormley N, Gilbert JA, Smith G, Knight R. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 2012 Aug;6(8):1621-4. doi: 10.1038/ismej.2012.8. Epub 2012 Mar 8. — View Citation

Carbone JW, Margolis LM, McClung JP, Cao JJ, Murphy NE, Sauter ER, Combs GF Jr, Young AJ, Pasiakos SM. Effects of energy deficit, dietary protein, and feeding on intracellular regulators of skeletal muscle proteolysis. FASEB J. 2013 Dec;27(12):5104-11. doi: 10.1096/fj.13-239228. Epub 2013 Aug 21. — View Citation

Carbone JW, McClung JP, Pasiakos SM. Skeletal muscle responses to negative energy balance: effects of dietary protein. Adv Nutr. 2012 Mar 1;3(2):119-26. doi: 10.3945/an.111.001792. Review. — View Citation

Cardello AV, Schutz HG, Lesher LL, Merrill E. Development and testing of a labeled magnitude scale of perceived satiety. Appetite. 2005 Feb;44(1):1-13. Epub 2004 Nov 13. Review. — View Citation

Carter CS, Braver TS, Barch DM, Botvinick MM, Noll D, Cohen JD. Anterior cingulate cortex, error detection, and the online monitoring of performance. Science. 1998 May 1;280(5364):747-9. — View Citation

Christensen PA, Jacobsen O, Thorlund JB, Madsen T, Møller C, Jensen C, Suetta C, Aagaard P. Changes in maximum muscle strength and rapid muscle force characteristics after long-term special support and reconnaissance missions: a preliminary report. Mil Med. 2008 Sep;173(9):889-94. — View Citation

Christiansen K, Knussmann R. Sex hormones and cognitive functioning in men. Neuropsychobiology. 1987;18(1):27-36. — View Citation

Clemmons DR, Smith-Banks A, Underwood LE. Reversal of diet-induced catabolism by infusion of recombinant insulin-like growth factor-I in humans. J Clin Endocrinol Metab. 1992 Jul;75(1):234-8. — View Citation

Coates JM, Gurnell M, Sarnyai Z. From molecule to market: steroid hormones and financial risk-taking. Philos Trans R Soc Lond B Biol Sci. 2010 Jan 27;365(1538):331-43. doi: 10.1098/rstb.2009.0193. Review. — View Citation

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 Mar;93(3):914-9. Epub 2007 Dec 26. — View Citation

Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav. 2006 Aug 30;89(1):71-84. Epub 2006 Jul 21. Review. — View Citation

Deplancke B, Vidal O, Ganessunker D, Donovan SM, Mackie RI, Gaskins HR. Selective growth of mucolytic bacteria including Clostridium perfringens in a neonatal piglet model of total parenteral nutrition. Am J Clin Nutr. 2002 Nov;76(5):1117-25. — View Citation

Dinges DF, Powell JW. Microcomputer analyses of performance on a portable, simple, visual RT task during sustained operations. Vol 171985:652-655.

Dulloo AG, Jacquet J, Girardier L. Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues. Am J Clin Nutr. 1997 Mar;65(3):717-23. — View Citation

Dulloo AG, Jacquet J, Montani JP. How dieting makes some fatter: from a perspective of human body composition autoregulation. Proc Nutr Soc. 2012 Aug;71(3):379-89. doi: 10.1017/S0029665112000225. Epub 2012 Apr 5. — View Citation

Ebstein RP, Israel S, Chew SH, Zhong S, Knafo A. Genetics of human social behavior. Neuron. 2010 Mar 25;65(6):831-44. doi: 10.1016/j.neuron.2010.02.020. Review. — View Citation

Fine BJ, Kobrick JL, Lieberman HR, Marlowe B, Riley RH, Tharion WJ. Effects of caffeine or diphenhydramine on visual vigilance. Psychopharmacology (Berl). 1994 Mar;114(2):233-8. — View Citation

Finkelstein JS, Yu EW, Burnett-Bowie SA. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013 Dec 19;369(25):2457. doi: 10.1056/NEJMc1313169. — View Citation

Forchielli ML, Walker WA. The effect of protective nutrients on mucosal defense in the immature intestine. Acta Paediatr Suppl. 2005 Oct;94(449):74-83. — View Citation

Friedl KE, Moore RJ, Hoyt RW, Marchitelli LJ, Martinez-Lopez LE, Askew EW. Endocrine markers of semistarvation in healthy lean men in a multistressor environment. J Appl Physiol (1985). 2000 May;88(5):1820-30. — View Citation

Goetz SM, Tang L, Thomason ME, Diamond MP, Hariri AR, Carré JM. Testosterone rapidly increases neural reactivity to threat in healthy men: a novel two-step pharmacological challenge paradigm. Biol Psychiatry. 2014 Aug 15;76(4):324-31. doi: 10.1016/j.biopsych.2014.01.016. Epub 2014 Jan 29. — View Citation

Greenman Y, Rouach V, Limor R, Gilad S, Stern N. Testosterone is a strong correlate of ghrelin levels in men and postmenopausal women. Neuroendocrinology. 2009;89(1):79-85. doi: 10.1159/000151768. Epub 2008 Aug 28. — View Citation

Grootjans J, Thuijls G, Verdam F, Derikx JP, Lenaerts K, Buurman WA. Non-invasive assessment of barrier integrity and function of the human gut. World J Gastrointest Surg. 2010 Mar 27;2(3):61-9. doi: 10.4240/wjgs.v2.i3.61. — View Citation

Henning PC, Margolis LM, McClung JP, Young AJ, Pasiakos SM. High protein diets do not attenuate decrements in testosterone and IGF-I during energy deficit. Metabolism. 2014 May;63(5):628-32. doi: 10.1016/j.metabol.2014.02.007. Epub 2014 Feb 17. — View Citation

Henning PC, Scofield DE, Spiering BA, Staab JS, Matheny RW Jr, Smith MA, Bhasin S, Nindl BC. Recovery of endocrine and inflammatory mediators following an extended energy deficit. J Clin Endocrinol Metab. 2014 Mar;99(3):956-64. doi: 10.1210/jc.2013-3046. Epub 2013 Dec 11. — View Citation

Hoyt RW, Opstad PK, Haugen AH, DeLany JP, Cymerman A, Friedl KE. Negative energy balance in male and female rangers: effects of 7 d of sustained exercise and food deprivation. Am J Clin Nutr. 2006 May;83(5):1068-75. — View Citation

Jéquier E, Acheson K, Schutz Y. Assessment of energy expenditure and fuel utilization in man. Annu Rev Nutr. 1987;7:187-208. Review. — View Citation

Jockenhövel F, Blum WF, Vogel E, Englaro P, Müller-Wieland D, Reinwein D, Rascher W, Krone W. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab. 1997 Aug;82(8):2510-3. — View Citation

Johnson RT, Breedlove SM. Human trust: testosterone raises suspicion. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11149-50. doi: 10.1073/pnas.1005376107. Epub 2010 Jun 10. — View Citation

Keo-Meier CL, Herman LI, Reisner SL, Pardo ST, Sharp C, Babcock JC. Testosterone treatment and MMPI-2 improvement in transgender men: a prospective controlled study. J Consult Clin Psychol. 2015 Feb;83(1):143-56. doi: 10.1037/a0037599. Epub 2014 Aug 11. — View Citation

Knapik JJ, Ang P, Meiselman H, Johnson W, Kirk J, Bensel C, Hanlon W. Soldier performance and strenuous road marching: influence of load mass and load distribution. Mil Med. 1997 Jan;162(1):62-7. — View Citation

Knapik JJ, Reynolds KL, Harman E. Soldier load carriage: historical, physiological, biomechanical, and medical aspects. Mil Med. 2004 Jan;169(1):45-56. Review. — View Citation

Kuczynski J, Lauber CL, Walters WA, Parfrey LW, Clemente JC, Gevers D, Knight R. Experimental and analytical tools for studying the human microbiome. Nat Rev Genet. 2011 Dec 16;13(1):47-58. doi: 10.1038/nrg3129. Review. — View Citation

Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest. 1993 Feb;91(2):391-6. — View Citation

Kvorning T, Andersen M, Brixen K, Madsen K. Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo-controlled, and blinded intervention study. Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1325-32. Epub 2006 Jul 25. — View Citation

Lakshman KM, Kaplan B, Travison TG, Basaria S, Knapp PE, Singh AB, LaValley MP, Mazer NA, Bhasin S. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. J Clin Endocrinol Metab. 2010 Aug;95(8):3955-64. doi: 10.1210/jc.2010-0102. Epub 2010 Jun 9. — View Citation

Lambert GP. Stress-induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci. 2009 Apr;87(14 Suppl):E101-8. doi: 10.2527/jas.2008-1339. Epub 2008 Sep 12. Review. — View Citation

Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE, Stuart GL, Strong DR, Brown RA. Evaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task (BART). J Exp Psychol Appl. 2002 Jun;8(2):75-84. — View Citation

Lieberman HR, Bathalon GP, Falco CM, et al. The Fog of War: Documenting Cognitive Decrements Associated with the Stress of Combat. 2002.

Lieberman HR, Bathalon GP, Falco CM, Kramer FM, Morgan CA 3rd, Niro P. Severe decrements in cognition function and mood induced by sleep loss, heat, dehydration, and undernutrition during simulated combat. Biol Psychiatry. 2005 Feb 15;57(4):422-9. — View Citation

Lieberman HR, Caruso CM, Niro PJ, Adam GE, Kellogg MD, Nindl BC, Kramer FM. A double-blind, placebo-controlled test of 2 d of calorie deprivation: effects on cognition, activity, sleep, and interstitial glucose concentrations. Am J Clin Nutr. 2008 Sep;88(3):667-76. — View Citation

Lieberman HR, Falco CM, Slade SS. Carbohydrate administration during a day of sustained aerobic activity improves vigilance, as assessed by a novel ambulatory monitoring device, and mood. Am J Clin Nutr. 2002 Jul;76(1):120-7. — View Citation

Lieberman HR, Tharion WJ, Shukitt-Hale B, Speckman KL, Tulley R. Effects of caffeine, sleep loss, and stress on cognitive performance and mood during U.S. Navy SEAL training. Sea-Air-Land. Psychopharmacology (Berl). 2002 Nov;164(3):250-61. Epub 2002 Sep 5. — View Citation

Lieberman HR, Thompson LA, Caruso CM, Niro PJ, Mahoney CR, McClung JP, Caron GR. The catecholamine neurotransmitter precursor tyrosine increases anger during exposure to severe psychological stress. Psychopharmacology (Berl). 2015 Mar;232(5):943-51. doi: 10.1007/s00213-014-3727-7. Epub 2014 Sep 16. — View Citation

Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, Veldhuis P, Gordon DA, Howard AD, Witcher DR, Geysen HM, Gaylinn BD, Thorner MO. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab. 2008 May;93(5):1980-7. doi: 10.1210/jc.2007-2235. Epub 2008 Mar 18. — View Citation

Lo S, Russell JC, Taylor AW. Determination of glycogen in small tissue samples. J Appl Physiol. 1970 Feb;28(2):234-6. — View Citation

Lohman TG, Harris M, Teixeira PJ, Weiss L. Assessing body composition and changes in body composition. Another look at dual-energy X-ray absorptiometry. Ann N Y Acad Sci. 2000 May;904:45-54. Review. — View Citation

Lotze M, Veit R, Anders S, Birbaumer N. Evidence for a different role of the ventral and dorsal medial prefrontal cortex for social reactive aggression: An interactive fMRI study. Neuroimage. 2007 Jan 1;34(1):470-8. Epub 2006 Oct 27. — View Citation

Luboshitzky R, Shen-Orr Z, Herer P. Middle-aged men secrete less testosterone at night than young healthy men. J Clin Endocrinol Metab. 2003 Jul;88(7):3160-6. — View Citation

Margolis LM, Murphy NE, Martini S, Spitz MG, Thrane I, McGraw SM, Blatny JM, Castellani JW, Rood JC, Young AJ, Montain SJ, Gundersen Y, Pasiakos SM. Effects of winter military training on energy balance, whole-body protein balance, muscle damage, soreness, and physical performance. Appl Physiol Nutr Metab. 2014 Dec;39(12):1395-401. doi: 10.1139/apnm-2014-0212. — View Citation

Margolis LM, Rood J, Champagne C, Young AJ, Castellani JW. Energy balance and body composition during US Army special forces training. Appl Physiol Nutr Metab. 2013 Apr;38(4):396-400. doi: 10.1139/apnm-2012-0323. Epub 2013 Apr 3. — View Citation

Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013 Mar 1;339(6123):1084-8. doi: 10.1126/science.1233521. Epub 2013 Jan 17. — View Citation

Mauras N, Hayes V, Welch S, Rini A, Helgeson K, Dokler M, Veldhuis JD, Urban RJ. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab. 1998 Jun;83(6):1886-92. — View Citation

McClung JP, Karl JP. Iron deficiency and obesity: the contribution of inflammation and diminished iron absorption. Nutr Rev. 2009 Feb;67(2):100-4. doi: 10.1111/j.1753-4887.2008.00145.x. Review. — View Citation

McNair DM, Lorr M, Droppleman LF. Profile of Mood States Manual. San Diego, CA: Educational and Industrial Testing Service; 1971.

Meng J, Mostaghel EA, Vakar-Lopez F, Montgomery B, True L, Nelson PS. Testosterone regulates tight junction proteins and influences prostatic autoimmune responses. Horm Cancer. 2011 Jun;2(3):145-56. doi: 10.1007/s12672-010-0063-1. — View Citation

Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO. A new predictive equation for resting energy expenditure in healthy individuals. Am J Clin Nutr. 1990 Feb;51(2):241-7. — View Citation

Moffat SD, Hampson E. A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology. 1996 Apr;21(3):323-37. — View Citation

Montani JP, Schutz Y, Dulloo AG. Dieting and weight cycling as risk factors for cardiometabolic diseases: who is really at risk? Obes Rev. 2015 Feb;16 Suppl 1:7-18. doi: 10.1111/obr.12251. Review. — View Citation

Morgenthaler T, Alessi C, Friedman L, Owens J, Kapur V, Boehlecke B, Brown T, Chesson A Jr, Coleman J, Lee-Chiong T, Pancer J, Swick TJ; Standards of Practice Committee; American Academy of Sleep Medicine. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep. 2007 Apr;30(4):519-29. — View Citation

Morley JE, Kaiser F, Raum WJ, Perry HM 3rd, Flood JF, Jensen J, Silver AJ, Roberts E. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7537-42. — View Citation

Muller M, Aleman A, Grobbee DE, de Haan EH, van der Schouw YT. Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology. 2005 Mar 8;64(5):866-71. — View Citation

Murphy MG, Plunkett LM, Gertz BJ, He W, Wittreich J, Polvino WM, Clemmons DR. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998 Feb;83(2):320-5. — View Citation

Nindl BC, Alemany JA, Kellogg MD, Rood J, Allison SA, Young AJ, Montain SJ. Utility of circulating IGF-I as a biomarker for assessing body composition changes in men during periods of high physical activity superimposed upon energy and sleep restriction. J Appl Physiol (1985). 2007 Jul;103(1):340-6. Epub 2007 Apr 5. — View Citation

Nindl BC, Barnes BR, Alemany JA, Frykman PN, Shippee RL, Friedl KE. Physiological consequences of U.S. Army Ranger training. Med Sci Sports Exerc. 2007 Aug;39(8):1380-7. — View Citation

Nindl BC, Friedl KE, Frykman PN, Marchitelli LJ, Shippee RL, Patton JF. Physical performance and metabolic recovery among lean, healthy men following a prolonged energy deficit. Int J Sports Med. 1997 Jul;18(5):317-24. — View Citation

Nindl BC, Leone CD, Tharion WJ, Johnson RF, Castellani JW, Patton JF, Montain SJ. Physical performance responses during 72 h of military operational stress. Med Sci Sports Exerc. 2002 Nov;34(11):1814-22. — View Citation

Nindl BC, Rarick KR, Castellani JW, Tuckow AP, Patton JF, Young AJ, Montain SJ. Altered secretion of growth hormone and luteinizing hormone after 84 h of sustained physical exertion superimposed on caloric and sleep restriction. J Appl Physiol (1985). 2006 Jan;100(1):120-8. Epub 2005 Sep 1. — View Citation

O'Carroll R, Shapiro C, Bancroft J. Androgens, behaviour and nocturnal erection in hypogonadal men: the effects of varying the replacement dose. Clin Endocrinol (Oxf). 1985 Nov;23(5):527-38. — View Citation

O'Connor DB, Archer J, Wu FC. Effects of testosterone on mood, aggression, and sexual behavior in young men: a double-blind, placebo-controlled, cross-over study. J Clin Endocrinol Metab. 2004 Jun;89(6):2837-45. — View Citation

Opstad PK. The hypothalamo-pituitary regulation of androgen secretion in young men after prolonged physical stress combined with energy and sleep deprivation. Acta Endocrinol (Copenh). 1992 Sep;127(3):231-6. — View Citation

Pagotto U, Gambineri A, Pelusi C, Genghini S, Cacciari M, Otto B, Castañeda T, Tschöp M, Pasquali R. Testosterone replacement therapy restores normal ghrelin in hypogonadal men. J Clin Endocrinol Metab. 2003 Sep;88(9):4139-43. — View Citation

Pasiakos SM, Austin KG, Lieberman HR, Askew EW. Efficacy and safety of protein supplements for U.S. Armed Forces personnel: consensus statement. J Nutr. 2013 Nov;143(11):1811S-1814S. doi: 10.3945/jn.113.176859. Epub 2013 Sep 11. — View Citation

Pasiakos SM, Cao JJ, Margolis LM, Sauter ER, Whigham LD, McClung JP, Rood JC, Carbone JW, Combs GF Jr, Young AJ. Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: a randomized controlled trial. FASEB J. 2013 Sep;27(9):3837-47. doi: 10.1096/fj.13-230227. Epub 2013 Jun 5. — View Citation

Pasiakos SM, Margolis LM, McClung JP, Cao JJ, Whigham LD, Combs GF, Young AJ. Whole-body protein turnover response to short-term high-protein diets during weight loss: a randomized controlled trial. Int J Obes (Lond). 2014 Jul;38(7):1015-8. doi: 10.1038/ijo.2013.197. Epub 2013 Oct 29. — View Citation

Pasiakos SM, Margolis LM, Orr JS. Optimized dietary strategies to protect skeletal muscle mass during periods of unavoidable energy deficit. FASEB J. 2015 Apr;29(4):1136-42. doi: 10.1096/fj.14-266890. Epub 2014 Dec 30. Review. — View Citation

Penev PD. Association between sleep and morning testosterone levels in older men. Sleep. 2007 Apr;30(4):427-32. — View Citation

Pescatello LS, Devaney JM, Hubal MJ, Thompson PD, Hoffman EP. Highlights from the functional single nucleotide polymorphisms associated with human muscle size and strength or FAMuSS study. Biomed Res Int. 2013;2013:643575. doi: 10.1155/2013/643575. Epub 2013 Dec 23. — View Citation

Plaisancie P, Ducroc R, El Homsi M, Tsocas A, Guilmeau S, Zoghbi S, Thibaudeau O, Bado A. Luminal leptin activates mucin-secreting goblet cells in the large bowel. Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G805-12. Epub 2006 Feb 2. — View Citation

Possemiers S, Verthé K, Uyttendaele S, Verstraete W. PCR-DGGE-based quantification of stability of the microbial community in a simulator of the human intestinal microbial ecosystem. FEMS Microbiol Ecol. 2004 Sep 1;49(3):495-507. doi: 10.1016/j.femsec.2004.05.002. — View Citation

Prevost M, Carrier ME, Chowne G, Zelkowitz P, Joseph L, Gold I. The Reading the Mind in the Eyes test: validation of a French version and exploration of cultural variations in a multi-ethnic city. Cogn Neuropsychiatry. 2014;19(3):189-204. doi: 10.1080/13546805.2013.823859. Epub 2013 Aug 13. — View Citation

Price JC, Holmes WE, Li KW, Floreani NA, Neese RA, Turner SM, Hellerstein MK. Measurement of human plasma proteome dynamics with (2)H(2)O and liquid chromatography tandem mass spectrometry. Anal Biochem. 2012 Jan 1;420(1):73-83. doi: 10.1016/j.ab.2011.09.007. Epub 2011 Sep 14. — View Citation

Ravussin Y, Koren O, Spor A, LeDuc C, Gutman R, Stombaugh J, Knight R, Ley RE, Leibel RL. Responses of gut microbiota to diet composition and weight loss in lean and obese mice. Obesity (Silver Spring). 2012 Apr;20(4):738-47. doi: 10.1038/oby.2011.111. Epub 2011 May 19. — View Citation

Roy TC, Ritland BM, Knapik JJ, Sharp MA. Lifting tasks are associated with injuries during the early portion of a deployment to Afghanistan. Mil Med. 2012 Jun;177(6):716-22. — View Citation

Roy TC. Diagnoses and mechanisms of musculoskeletal injuries in an infantry brigade combat team deployed to Afghanistan evaluated by the brigade physical therapist. Mil Med. 2011 Aug;176(8):903-8. — View Citation

Salmimies P, Kockott G, Pirke KM, Vogt HJ, Schill WB. Effects of testosterone replacement on sexual behavior in hypogonadal men. Arch Sex Behav. 1982 Aug;11(4):345-53. — View Citation

Shukitt-Hale B, Askew EW, Lieberman HR. Effects of 30 days of undernutrition on reaction time, moods, and symptoms. Physiol Behav. 1997 Oct;62(4):783-9. — View Citation

Silverman I, Kastuk D, Choi J, Phillips K. Testosterone levels and spatial ability in men. Psychoneuroendocrinology. 1999 Nov;24(8):813-22. — View Citation

Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol (Oxf). 1981 Jan;14(1):49-61. — View Citation

Sonoyama K, Fujiwara R, Takemura N, Ogasawara T, Watanabe J, Ito H, Morita T. Response of gut microbiota to fasting and hibernation in Syrian hamsters. Appl Environ Microbiol. 2009 Oct;75(20):6451-6. doi: 10.1128/AEM.00692-09. Epub 2009 Aug 21. — View Citation

Spiering BA, Kraemer WJ, Vingren JL, Ratamess NA, Anderson JM, Armstrong LE, Nindl BC, Volek JS, Häkkinen K, Maresh CM. Elevated endogenous testosterone concentrations potentiate muscle androgen receptor responses to resistance exercise. J Steroid Biochem Mol Biol. 2009 Apr;114(3-5):195-9. doi: 10.1016/j.jsbmb.2009.02.005. Epub 2009 Feb 21. — View Citation

Spiro A, Butcher JN, Levenson RM, Aldwin CM, Bossé R. Change and stability in personality: A 5-year study of the MMPI-2 in older men. In: Butcher JN, ed. Fundamentals of MMPI-2: Research and application Minneapolis, MN: University of Minnesota Press; 2000:443-462.

Stanton SJ, Liening SH, Schultheiss OC. Testosterone is positively associated with risk taking in the Iowa Gambling Task. Horm Behav. 2011 Feb;59(2):252-6. doi: 10.1016/j.yhbeh.2010.12.003. Epub 2010 Dec 15. — View Citation

Stunkard AJ, Messick S. The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res. 1985;29(1):71-83. — View Citation

Sumithran P, Proietto J. The defence of body weight: a physiological basis for weight regain after weight loss. Clin Sci (Lond). 2013 Feb;124(4):231-41. doi: 10.1042/CS20120223. Review. — View Citation

Teshima CW, Meddings JB. The measurement and clinical significance of intestinal permeability. Curr Gastroenterol Rep. 2008 Oct;10(5):443-9. Review. — View Citation

Thorlund JB, Jakobsen O, Madsen T, Christensen PA, Nedergaard A, Andersen JL, Suetta C, Aagaard P. Changes in muscle strength and morphology after muscle unloading in Special Forces missions. Scand J Med Sci Sports. 2011 Dec;21(6):e56-63. doi: 10.1111/j.1600-0838.2010.01149.x. Epub 2010 Jun 18. — View Citation

Uhart M, McCaul ME, Oswald LM, Choi L, Wand GS. GABRA6 gene polymorphism and an attenuated stress response. Mol Psychiatry. 2004 Nov;9(11):998-1006. — View Citation

van Honk J, Tuiten A, Verbaten R, van den Hout M, Koppeschaar H, Thijssen J, de Haan E. Correlations among salivary testosterone, mood, and selective attention to threat in humans. Horm Behav. 1999 Aug;36(1):17-24. — View Citation

van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull. 2008 Nov;34(6):1095-105. doi: 10.1093/schbul/sbn101. Epub 2008 Aug 20. Review. — View Citation

Vartanian O, Mandel DR, Duncan M. Money or life: Behavioral and neural context effects on choice under uncertainty. Journal of Neuroscience, Psychology, and Economics. 2011;4(1):25-36.

Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N; Testosterone Gel Study Group. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000 Aug;85(8):2839-53. — View Citation

Weiner C. Anticipate and communicate: Ethical management of incidental and secondary findings in the clinical, research, and direct-to-consumer contexts (December 2013 report of the Presidential Commission for the Study of Bioethical Issues). Am J Epidemiol. 2014 Sep 15;180(6):562-4. doi: 10.1093/aje/kwu217. Epub 2014 Aug 22. — View Citation

Weiner IB, Greene RL. Handbook of Personality Assessment. Hoboken, NJ: Wiley; 2006.

WEIR JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949 Aug;109(1-2):1-9. — View Citation

Welsh TT, Alemany JA, Montain SJ, Frykman PN, Tuckow AP, Young AJ, Nindl BC. Effects of intensified military field training on jumping performance. Int J Sports Med. 2008 Jan;29(1):45-52. Epub 2007 Sep 18. — View Citation

Wittert G. The relationship between sleep disorders and testosterone in men. Asian J Androl. 2014 Mar-Apr;16(2):262-5. doi: 10.4103/1008-682X.122586. Review. — View Citation

Wright ND, Bahrami B, Johnson E, Di Malta G, Rees G, Frith CD, Dolan RJ. Testosterone disrupts human collaboration by increasing egocentric choices. Proc Biol Sci. 2012 Jun 7;279(1736):2275-80. doi: 10.1098/rspb.2011.2523. Epub 2012 Feb 1. — View Citation

Wycherley TP, Moran LJ, Clifton PM, Noakes M, Brinkworth GD. Effects of energy-restricted high-protein, low-fat compared with standard-protein, low-fat diets: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2012 Dec;96(6):1281-98. doi: 10.3945/ajcn.112.044321. Epub 2012 Oct 24. Review. — View Citation

Zak PJ, Kurzban R, Ahmadi S, Swerdloff RS, Park J, Efremidze L, Redwine K, Morgan K, Matzner W. Testosterone administration decreases generosity in the ultimatum game. PLoS One. 2009 Dec 16;4(12):e8330. doi: 10.1371/journal.pone.0008330. — View Citation

Zhang L, Rao F, Wessel J, Kennedy BP, Rana BK, Taupenot L, Lillie EO, Cockburn M, Schork NJ, Ziegler MG, O'Connor DT. Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: prediction of catecholamines and response to stress in twins. Physiol Genomics. 2004 Nov 17;19(3):277-91. Epub 2004 Sep 14. — View Citation

* Note: There are 132 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Body Composition at the End of Each Study Phase	Height was measured using a stadiometer. Weight was measured using a calibrated digital scale. Body composition was determined using dual-energy X-ray absorptiometry. These data were used to calculate fat-free body mass, fat mass, and total body tissue mass.	end of each study phase: Day 11 for Phase 1, Day 39 for Phase 2, up to Day 85 for Phase 3