Doi:10.1016/j.metabol.2004.12.010

Metabolism Clinical and Experimental 54 (2005) 657 – 668 Cortitrol supplementation reduces serum cortisol William J. KraemerT, Duncan N. French, Barry A. Spiering, Jeff S. Volek, Matthew J. Sharman, Nicholas A. Ratamess, Daniel A. Judelson, Ricardo Silvestre, Greig Watson, Ana Go´mez, Carl M. Maresh Human Performance Laboratory, Department of Kinesiology and Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA Received 9 August 2004; accepted 14 December 2004 The supplement Cortitrol was formulated to mitigate the cortisol response to physiological and psychological stress. Therefore, the purpose of this study was to examine the effects of Cortitrol on serum cortisol concentrations before, during, and after a high-intensityresistance exercise protocol (EX) and a resting control day (REST). We used a matched, balanced, randomized, double-blind, placebo-controlled, cross-over design. Blood samples were obtained at matching time points during EX and REST. Cortitrol significantly ( P b .05)reduced cortisol area under the curve concentrations during REST. During EX, Cortitrol reduced cortisol concentrations at 20, 10, and 0minutes pre-exercise, at mid-exercise, immediately post-exercise, and at 5 minutes post-exercise. In addition, serum cortisol and plasmaadrenocorticotropin hormone area under the curve concentrations during EX were significantly lower after Cortitrol than placebo.
Furthermore, Cortitrol significantly reduced free radical production. This was indicated by significantly lower plasma malondialdehydeconcentrations at the 65-minute post-exercise time point during REST, and at pre-exercise, immediate post-exercise, and 65 minutes post-exercise during EX. Serum total testosterone, free testosterone, dehydroepiandrosterone, and growth hormone showed exercise-inducedincreases but no treatment effects. These data demonstrate that Cortitrol was effective in modulating the physiological stress responses ofexercise from the anticipatory rises before physical stress and into early recovery by reducing cortisol and associated free radical production.
D 2005 Elsevier Inc. All rights reserved.
physical training, labor in the work place, or chronicphysiological stress.
When human beings are confronted with physiological There are 2 components of the supplement regimen and/or psychological stress the adrenal gland secretes tested. The first component is a general vitamin/mineral cortisol. This response increases glucose and fatty acid combination of pantothenic acid (30 mg), pyridoxine concentrations in the blood and stimulates gluconeogenesis (10 mg), riboflavin (8.5 mg), thiamine (7.5 mg), vitamin to prepare the body for bfight or flight.Q Although cortisol is C (250 mg), calcium (100 mg), and magnesium (100 mg).
necessary for normal physiological function, chronic ele- B vitamins (pantothenic acid, pyridoxine, riboflavin, and vations have a negative impact on muscle and immune cell thiamine) were added to prevent deficiencies common in function and bone metabolism. Nutritional interventions active individuals which have been shown to decrease aimed at partially attenuating the cortisol response would prove valuable for those faced with, for example, intense 2max, onset of blood lactate accumulation, peak power, and mean power Vitamin C supplementation has thepotential to reduce blood pressure, cortisol, and subjectiveresponses to acute psychological stress in healthy subjectsas well as exercise stress responses in competitive T Corresponding author. Human Performance Laboratory, Department weightlifters Calcium intake is essential for minimizing of Kinesiology, University of Connecticut, Storrs, CT 06269-1110, USA.
Tel.: +1 860 486 6892; fax: +1 860 486 6898.
bone loss and osteoporosis a disease common among E-mail address: [email protected] (W.J. Kraemer).
individuals with persistently elevated cortisol levels 0026-0495/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.metabol.2004.12.010 W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 Finally, chronic stress may exacerbate preexisting magne- marathon had a decreased inflammatory response, cortisol/ sium deficiencies, which can lead to impaired ergy dehydroepiandrosterone (DHEA) ratio, and imm metabolism and decreased physical work capacity [7].
pression during the postmarathon recovery period [16].
The second component of the supplement is Cortitrol, a Although cortisol is necessary to respond to physiological proprietary herbal anticortisol blend containing magnolia stress, chronic elevation of cortisol may have negative effects bark extract (Magnolia officialis), l-theanine (from Camillia on a host of target tissues, such as reduced immune cell sinensis), Epimedium extract (Epimedium koreanum), function, protein wasting in muscle, and suboptimal bone phophatidylserine (soy derived), and b-sitosterol. Limited metabolism. However, complete elimination of the overt data exist on the effectiveness of these herbal supplements; cortisol response to stress would be physiologically inap- however, preliminary studies show promising results.
propriate for normal human health. Thus, Cortitrol was Magnolol, a phenolic constituent of magnolia bark, has designed and formulated to reduce the magnitude of the been shown to suppress cortical serotonin (5-hydroxytryp- overt stress response and absolute cortisol concentrations.
tamine) release , which may be advantageous because Intense resistance exercise and training has been shown to serotonin plays a role in stress and anxiety–related disorders cause dramatic increases in cortisol levels Further- l-theanine, commonly found in tea, may prime blood more, athletes show elevated cortisol levels in anticipation of T cells and provide natural resistance to infection and intense physical challenge Therefore, high-intensity promote brain a-wave and suppress b-wave activity resistance exercise provides an ideal forum to test the Epimedium has been shown to lower cortisol levels in purported benefits of Cortitrol. The purpose of this investi- animal models Monteleone et al showed that gation was to determine the efficacy of Cortitrol to influence phosphatidylserine supplementation attenuated the cortisol cortisol responses to an intense physical exercise stress response to physical stress in healthy men. Finally, subjects model in human beings known to dramatically increase supplementing with b-sitosterol before competing in a cortisol concentrations in the blood. We hypothesized that A. ======================================================================= Blood
Sample
Diet
Records
=============================================== 4 x Squat 4 x Bench
4 x Row 4 x Press
Blood
Sample
DEXA
Fig. 1. A, Experimental design. A balanced, randomized, double-blind, placebo-controlled, cross-over design was used to determine the effects of Cortitrol. Cindicates control day; E, exercise day. B, Testing sequence during exercise testing days. Blood samples were obtained at matching time points during restingcontrol days. DEXA indicates dual-energy x-ray absorptiometry.
W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 supplementation would result in decreased cortisol concen- only 10 repetitions to be performed but both experimental trations before, during, and after the exercise challenge.
workouts used very similar if not identical resistances in theworkout sequences because of arization andpractices of the experimental protocol [18,21]. To maximally stimulate all major muscle groups, the back squat, bench press, bent over row, and shoulder press exercises were used.
Two minutes of rest was allowed between each set and The Institutional Review Board for use of Human exercise. This protocol has been found to produce high phys- Subjects in Research at the University of Connecticut iological stress, as evidenced by cortisol 00 nmol/L) approved all study procedures before its initiation. Twenty- and lactate concentrations ( N14 mmol/L) Blood was one men volunteered to participate and gave written collected at 30 minutes (À30), 20 minutes (À20), and 10 consent after being informed of the risks associated with minutes (À10) pre-exercise, immediately before exercise the study. All subjects acted as their own controls with the (PRE), at the midpoint of the exercise protocol (MID), within-group design used in this study. Subjects were immediately post-exercise (IP), and at 5 minutes (+5), 10 healthy, college-aged men with resistance training experi- minutes (+10), 15 minutes (+15), 25 minutes (+25), 35 ence of 4 years or more. Mean (FSD) age and height were minutes (+35), 45 minutes (+45), 55 minutes (+55), and 65 21.1 F 1.2 years and 180.5 F 7.0 cm, respectively. Each minutes (+65) after exercise. Testing procedures for REST subject was specifically instructed to maintain their indi- (including duration, timing and number of blood draws, and vidual exercise routine (frequency, duration, and intensity) time of day) were identical. All treatment sessions were during the study, which was verified through evaluation of performed within the same identical time of day window physical activity diaries. Each subject was tested for (8:00 to 10:30 am) to reduce the influence of normal individual 1 repetition maximum (RM) using previously circadian variations, which can add to experimental variance.
described methods One RM of the back squat, bench After completion of EX and REST protocols, subjects were press, bent over row, and shoulder press exercises were crossed-over (into either the treatment or placebo group) and 130.8 F 27.4, 112.9 F 21.2, 90.2 F 17.5, and 72.1 F 11.3 Whole body composition was assessed using fan-beam A matched, balanced, randomized, double-blind, place- dual-energy x-ray absorptiometry (Prodigy, Lunar Corpo- bo-controlled, cross-over design was used to determine the ration, Madison, Wis). Subjects were positioned on the effects of Cortitrol on serum cortisol concentrations (see dual-energy x-ray absorptiometry according to the manu- Subjects were matched according to age, body size, facturer’s guidelines having removed all metallic objects and training experience. All subjects used physical activity from their body. Whole body analysis of fat tissue, lean diaries and food diaries to replicate lifestyle patterns for the tissue, and bone mineral content was assessed according to 3 days before each testing protocol. All subjects participated anatomical landmarks by the same technician using in several familiarization sessions before exercise testing to computer algorithms (enCORE version 6.00.270). Coeffi- reduce the experimental variance from learning effects and cients of variation for lean body mass and fat mass on to expose subjects to the physical challenge of the protocol.
repeat scans with repositioning within a group of male Resting baseline measures were obtained before (V-1) and subjects in our laboratory were 0.4% and 1.4%, respective- after (V-2) 1 week of supplementation following the placebo ly. The same experienced technician performed all measure- and Cortitrol conditions to determine measurement stability ments throughout the study period. Body mass was of the dependent variables. Subjects were then asked to report measured to the nearest 0.01 kg using an electronic to the laboratory on 2 separate occasions for each condition: scale (American Business Equipment Company, Inc, New once for a resistance training exercise challenge (EX) and Holland, Pa). Scans were performed on all subjects at 4 time once for a resting control day (REST). Treatment order wasbalanced and randomized; REST proceeded EX by 48 hours.
The EX protocol consisted of 4 sets of 10 RM using 4 Pre- and post-supplementation body composition and bone characteristics different exercises. A 10RM (the amount of weight that allowed only 10 repetitions to be performed) was determined during familiarization sessions and the resistances used for each set of every exercise were established with ICC R’s of more than 0.98 for 2 consecutive exercise sessions. The goal of the familiarizations was to create a reliable workout that could be highly replicated to produce a similar if not identical physiological stress response During the experimental workout, resistances were reduced to allow W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 points during the study: immediately before and on the similar foods for 3 days before the exercise bout for each seventh day of the supplementation protocol for both the phase. A registered dietician and associated staff counseled placebo and treatment conditions. No significant changes in and supervised the subjects to ensure no nutritional body compoobserved during the course of the variation would confound the dependent variables. To assist participants in duplicating their diet during phase 1and 2, subjects completed detailed 3-day diet diary records during both periods. Copies were made of phase 1 diet To possible confounding effects of diet on records and returned to subjects during phase 2 to enhance cortisol [22,23], subjects were instructed to consume reproducibility. Food diaries were analyzed for energy and Resting Control
Cortitrol
Exercise Protocol
Cortitrol
Fig. 2. A, Cortisol concentrations during the resting control day. *P b .05, significantly greater than corresponding Cortitrol value. #P b .05, significantlylower than corresponding Cortitrol value. Data are expressed as mean F SE. Insert, Area under the curve comparison for resting day. *P b .05 fromcorresponding placebo condition. B, Cortisol concentrations during the exercise challenge day. *P b .05, significantly different than corresponding placebovalue. Data are expressed as mean F SE. Insert, Area under the curve comparison for exercise challenge day. *P b .05 from corresponding placebo condition.
W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 Resting Control
Cortitrol
ACTH (pmol
Exercise Protocol
Cortitrol
ACTH (pmol
Fig. 3. A, Corticotropin concentrations during the resting control day. *P b .05 from corresponding placebo condition. B, Corticotropin concentrations duringthe exercise challenge day. *P b .05 from corresponding placebo condition. #P b .05 from corresponding pre-exercise time point. Data are expressed asmean F SE.
macro/micronutrient content with NUTRITIONIST PRO samples were assayed in duplicate and were decoded only (version 1.3, First Databank Inc, The Hearst Corporation, after analyses were completed (ie, blinded analysis proce- dure). For all procedures, samples were thawed only oncebefore analysis. The minimum detection limits for cortisol, total and free testosterone, DHEA, and corticotropin were Serum concentrations of cortisol, total and free testos- 2.76 nmol/L, 0.14 nmol/L, 0.66 nmol/L, 0.346 nmol/L and terone, and DHEA were determined in duplicate using 0.264 pmol/L, respectively. In all cases, intra-assay and commercially available enzyme immunoassay kits (Diag- nostic Systems Laboratories, Webster, Tex) according to the Plasma growth hormone (GH) concentrations were manufacturer’s procedures. Plasma corticotropin concentra- determined in duplicate using an 125I liquid-phase immu- tions were determined using enzyme-linked immunosorbent noradiometric assay (Nichols Institute Diagnostics, San assay (Diagnostic Systems Laboratories, Webster, Tex). All Juan, Capistrano, Calif). This commercially available W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 immunoradiometric assay uses 2 monoclonal antibodies of previously described [24,25] Briefly, 50 lL of unknown high affinity and specificity for GH, each detecting a sample and MDA standard (0.61-19.44 lmol/L; 1,1,2,2- different epitope on the GH molecule. One of the antibodies tetraethoxypropane standards) were pipetted into polypro- was labeled for detection, whereas the other was coupled to pylene test tubes. Then they were combined with 0.75 mL biotin. The sensitivity for this assay using the Bo (2 SD) of 0.44 mol/L phosphoric acid stock solution and 0.25 mL method was 0.04 ng/mL. Intra-assay variances for GH of 42 mmol/L thiobarbituric acid (0.6 g of 4,6-dihydroxy- thiopyrimidine in 100 mL of dH2O). Samples were further Plasma malondialdehyde (MDA) concentrations were diluted using 0.45 mL dH2O. All test tubes were then determined using a thiobarbituric acid assay procedure as capped, sealed tight, and placed in a preheated water bath at Resting Control
Cortitrol
MDA (mmol
Exercise Protocol
Cortitrol
MDA (mmol
Fig. 4. A, Plasma MDA concentrations during the resting control day at the time points corresponding to pre-exercise (Pre), immediately post-exercise (IP), and65 minutes post-exercise (65). *P b .05 from corresponding placebo condition. B, MDA responses during the exercise challenge day. *P b .05 fromcorresponding Cortitrol condition; #P b .05 from the corresponding treatment’s pre-exercise value; ^P b .05 from plasma MDA concentrations resting daycontrol values. Data are expressed as mean F SE.
W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 1008C for 60 minutes. After heating, samples were removed (21% F 2% and 23% F 5%). This minimized the impact of from the water bath and immediately placed into an ice dietary variation on endocrine responses between the 2 water bath (08C) until analysis. Samples remained on ice for treatment conditions. The dietary records of all participants no longer than 30 minutes before analysis; 1.5 mL of Me- revealed that they had normal eating patterns; no fad diets NaOH stock solution was then added to all boiled samples and/or signs or eating disorders were revealed.
and standards. All tubes were recapped, vortexed, and There were no pre-supplementation differences between centrifuged at 3500 rpm for 5 minutes to sediment the conditions in serum cortisol concentrations (placebo: precipitated plasma proteins. Plasma concentrations of F 22.94 nmol/L; Cortitrol: 440.2 F 142.3 nmol/L).
MDA were determined in duplicate. One-millimeter extract Fig. 2A shows pairwise differences between placebo and of protein-free plasma was removed from each test tube Cortitrol at À30, À10, IP, +35, and +55 during REST. The without disturbing the sedimented precipitate. All samples insert of demonstrates that cortisol AUC concen- and standards were transferred to 1.5-mL cuvettes and the trations during REST were significantly lower for the absorbance was read at 532 nm using a spectrophotometer Cortitrol supplementation condition.
(Spectronic 401, Spectronic Instruments Inc, Rochester,NY). To eliminate inter-assay variance, all samples for thisassay were analyzed in the same assay run. In all cases, Table 2Values for plasma glucose and lactate during resting control and intra-assay variances were less than 10%.
Plasma glucose and lactate concentrations were deter- mined using an automated glucose/lactate analyzer (2300 Stat glucose/l-lactate analyzer, YSI, Inc, Yellow Springs,Ohio). Hemoglobin was analyzed in triplicate from whole blood using the cyanmethemoglobin method (Sigma Diag- nostics, St Louis, Mo); hematocrit was analyzed in triplicate from whole blood via microcentrifugation and microcapil- lary technique. Plasma volume shifts after the workout were calculated using the formula of Dill and Costill Paired-sample t tests were used to examine differences between the 2 days of baseline resting values. Area under the curve (AUC) analyses were completed using standard trapezoidal statistical methods. Two-way analysis of vari- ance with repeated measures was used to examine pairwise differences in hormonal concentrations and a 2-way analysis of variance (2 groups  2 conditions) was used to evaluate the AUC data. Appropriate post hoc tests (ie, Fisher LSD or Tukey tests) were used when a significant F score resulted.
All linear assumptions were tested and, when appropriate,log10 transformations were used and the data were reanalyzed. Using nQuery Advisor software (Statistical Solutions, Saugus, Mass), the statistical power for the n size used ranged from 0.80 to 0.90. Significance in this There was no significant plasma volume shift pre- to post-exercise for either condition (placebo: +0.56% F 5.51% placebo; Cortitrol: +4.12% F 7.26%, P N .05). This was likely because of ad libitum water intake during the rest There were no significant differences between Cortitrol and placebo supplementation, respectively, for dietary energy (9517 F 3756 and 10752 F 4246 kJ), and the percent energy from carbohydrate (48% F 8% and 43% F a P b .05 from corresponding resting control day time point.
13%), fat (31% F 9% and 34% F 12%), and protein b P b .05 from corresponding pre-exercise value.
W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 Table 3Values for total testosterone, free testosterone, and DHEA during resting control and exercise days a P b .05 from corresponding Cortitrol condition.
b P b .05 from corresponding resting control day time point.
c P b .05 from corresponding pre-exercise value.
During EX, subjects had significantly lower cortisol AUC between the 2 conditions (placebo: 127.6 F 69.7 concentrations after Cortitrol supplementation than placebo pmol/L; Cortitrol: 131.7 F 73.3 pmol/L). Corticotropin at À20, À10, PRE, MID, IP, and +5 (Furthermore, responses to EX are presented in As expected, total exposure to absolute molar concentrations of cortisol, plasma corticotropin significantly increased in response to as demonstrated by AUC analysis, was significantly lower EX and concentrations were elevated above PRE values during the Cortitrol phase of the trial than the placebo phase through +55. Cortitrol treatment conditions were lower than (insert). There was a significant increase in cortisol placebo at +5 and +10. Corticotropin was significantly greater during EX than during REST. Corticotropin AUC Corticotropin responses are presented in There was significantly lower for Cortitrol than placebo (placebo: were no significant differences between the resting baseline 233.1.6 F 142.9 pmol/L; Cortitrol: 209.0 F 117.2 pmol/L).
measures. In general, there were no significant differences shows the MDA responses during the REST.
between REST values, although a significant difference was Significant differences were noted at +65. presents found at À20 (see No differences were observed in MDA data for EX. MDA values at PRE, IP, and +65 for W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 Cortitrol were significantly lower than placebo. Cortitrol Androgen concentration values are shown in Table 3.
values were significantly lower during EX than REST.
Total testosterone, free testosterone, and DHEA all followed There was an exercise-induced increase in MDA for both a similar response pattern. No differences between the 2 baseline days (V-1 and V-2) or during REST were apparent.
Table 2 presents the metabolic profile of plasma glucose During EX, no significant differences between conditions and lactate. No significant changes were noted in either were observed over the pre-exercise time frame. Significant variable during the baseline days (V-1 and V-2) or REST. As exercise-induced increases were observed from MID to +35 expected, plasma glucose and lactate were significantly in both conditions. All post-exercise values were signifi- elevated above PRE values post-exercise. Glucose values cantly higher than corresponding REST values. Placebo did not return to PRE values until +45; lactate values DHEA values were significantly lower than Cortitrol values remained significantly elevated above PRE values through +65. Plasma glucose values for EX were significantly higher than corresponding REST values from MID to +45. Plasma significant differences were observed over the baseline days lactate values for EX were significantly higher than or during REST for either condition. There were significant corresponding REST values from MID to +65.
exercise-induced increases in GH during EX compared toREST. During EX, there were significant pre- to post-exercise increases in GH concentration.
Table 4Mean (FSD) values for GH during resting control and exercise days It should be clear that the primary purpose of this study was to examine the ability of Cortitrol to modulate cortisol concentrations resulting from performance of a resistance exercise physical stress model. How any reductions in cortisol would impact physiological adaptations in various target tissue (eg, muscle and cell) cannot be determined with this experimental design and requires further experimenta- tion. Thus, we wanted to know if Cortitrol could influence the stress response. We know that cortisol plays important regulatory roles in various physiological functions and complete elimination of the catabolic response would not be optimal in homeostatic regulation. It is also important to understand that elimination of the cortisol response to physical stress would not be optimal to physiological adaptations. However, positive changes in muscle size development have occurred with reductions of cortisol over the first 8 weeks of resistance training Nevertheless, when cortisol is produced in excess, receptors beyond the primary targets are exposed to higher than normal molar concentrations of cortisol producing effects that may in fact be counterproductive to optimal tissue repair and remodeling (eg, reductions in immune cell activation in the attempt to conserve glycogen breakdown in the muscle yet inhibit repair with limited B-T-cell function and macrophage abilities to clean up degraded proteins in muscle). It is the chronic elevations of cortisol beyond normal concentrations that are most concerning to optimal physiological function and can have a negative impact on many target tissues including muscle, bone, and immune cells. We wanted to create an acute stress response with high concentrations of cortisol using our bstress modelQ of high-intensity resistance exercise to determine the influence of Cortitrol supplemen- tation on the cortisol response. This was done to determine the impact of the dietary supplement on a known physio- logical stress response of exercise to gain data on its P b .05 from corresponding resting control day time point.
b P b .05 from corresponding pre-exercise and baseline values.
physiological efficacy but its role in adaptive responses W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 cannot be determined from this experimental design. Data exposure measure. Reduced corticotropin AUC for Cortitrol from this investigation show that Cortitrol plays an important indicated subtle alterations of the tropic hormone signal modulatory role in dramatically reducing cortisol release during EX. These data are consistent with a lower before, and immediately after intense resistance hypothalamic-pituitary signal for cortisol production, sup- exercise (Fig. 2). Furthermore, the accumulated reduction in porting a mechanism related to the second component of cortisol over the 95-minute block of time on both the REST Cortitrol: the proprietary herbal combination containing and EX days suggests that Cortitrol reduces the total tissue magnolia bark, l-theanine, Epimedium, phosphatidylserine, exposure to cortisol. A reduction in free radical formation, as and b-sitosterol. In particular, phosphatidylserine may have measured by plasma MDA values, was also observed between the treatment conditions during EX. Thus, this Monteleone et al showed that, in addition to study gives initial insight into the influence of Cortitrol as a reduced cortisol concentrations, phosphatidylserine supple- general modulator of the adrenal stress response.
mentation attenuated the corticotropin response to physical The findings of this study should be viewed as the effects stress in healthy men. Our data indicate that part of the of a composite supplementation formula consisting of cortisol stress response, which was altered by the Cortitrol various nutritional attributes, which together, work to reduce treatment, was mediated by subtle changes in the secretion physiological stress. This formulation consists of a general of the regulatory hormone corticotropin.
vitamin/mineral complex and a proprietary blend of herbal Of particular interest was the differential responses of the compounds with known anticortisol effects Cortitrol and placebo treatments with regard to oxygen Both components may be necessary to mediate the observed reactive species formation, as measured by MDA concen- trations (see Fig. 4). This is a novel and unique finding that A dearth of information exists as to the role of nutritional may have dramatic ramifications because free radical supplementation to impact stress responses of cortisol.
production after exercise is known to produce chemical Vitamin C has been implicated in reducing cortisol damage to various target tissues. Although speculative, the responses to physical exercise In prior work using significant reduction in MDA could be due to one or more resistance exercise, Marsit et al showed a subtle of the antioxidant components of Cortitrol. One of the reduction in cortisol after supplementation with 1000 mg naturally occurring bioactive derivatives identified in vitamin C 24 hours before exercise. The treatment regimen magnolia officialis is the biphenolic compound magnolol, used in the present study provided 250 mg of vitamin C, which has been shown to be a potent antioxidant suggesting that ascorbic acid may have been a partial b-Sitosterol has also been shown to have antioxidant contributor to the positive effects observed in resting properties that protect against lipid peroxidation Some cortisol concentrations. In addition, magnolia bark extract, studies also show vitamin C increases serum oxygen-radical because of its antioxidant capacity and phosphatidyl- absorbance capacity Thompson et al specifi- serine, because of its effects on neuroendocrine responses to cally reported a reduction in plasma MDA during recovery exercise may have also contributed to the reduction from exercise after vitamin C supplementation. The precise role of cortisol in mediating the reduction in MDA remains It is interesting to note that Cortitrol attenuated the unclear. It is plausible that these other antioxidant com- cortisol response exclusively during the pre-exercise and pounds worked alone or in concert to reduce MDA early recovery period during EX, whereas no differences independent of any effect on circulating cortisol. Alterna- were apparent from +10 to +65. Subjects typically display tively, there is some indication that elevated cortisol an anticipatory rise in cortisol before exercise because of increases lipid peroxidation and thus the decrease in psychological fear of intense physical challenge cortisol would be associated with lower MDA levels. This Inherent to this model was the use of formal practice of finding implicates the role of Cortitrol in tissue repair and the exercise challenge to specifically familiarize each recovery, as well as in adrenal stress reduction.
subject with the dramatic physical demands of the exercise The responses of plasma glucose and lactate to EX were session Cortitrol supplementation diminished the consistent between conditions. Dramatic increases in plasma magnitude of the anticipatory response and reduced cortisol lactate ( N15 mmol/L) demonstrated the extreme metabolic concentrations into early recovery. These subtle effects stress response to the exercise challenge Bush et al implicate a physiological mechanism that does not disrupt has shown that high force exercise produces large cortisol’s important hormonal feedback roles in response to, lactate and epinephrine responses, which in part stimulate and recovery from, exercise (eg, glucose metabolism).
further release of cortisol. Lactate is correlated to epineph- The tropic hormone corticotropin demonstrated no rine responses after exercise stress however, Cortitrol significant differences in the stimulatory signals to ste- had no impact on metabolic responses (Our data roidogenesis during REST. Pulsatility of corticotropin may suggest the mechanism of Cortitrol is related to the adrenal exert a major trophic effect but we did not measure corticotropin pulsatility in this study. Owing to this Resistance exercise has been classically shown to limitation we calculated AUC to act as a composite increase hypothalamic-pituitary gonadal hormones W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 In general, no significant changes in androgen concentra- a nutritional supplement. This investigation also opens the tions were between Cortitrol and placebo con- door to many avenues of future research.
ditions (see Table 3). However, significantly lower cortisolvalues resulted in reduced cortisol/DHEA and increased testosterone/cortisol ratio, which would indicate a ganabolic environment during these time points [40].
This study was funded in part by a grant from Reduced cortisol/DHEA ratio has been observed previously Pharmanex, an NSE Company, Provo, Utah.
in marathon runners supplementing with b-sitosterol beforethe competition. This was associated with decreasedinflammatory response and cortisol concentrations during the marathon recovery period In our study, the impact [1] Manore MM. Effect of physical activity on thiamine, riboflavin, and of such a response on inflammatory cytokines and immune vitamin B-6 requirements. Am J Clin Nutr 2000;72:598S - 606S.
cells remains speculative. However, future research may [2] van der Beek EJ, van Dokkum W, Wedel M, et al. Thiamin, riboflavin and vitamin B6: impact of restricted intake on physical performance in wish to investigate this potential role of Cortitrol. Never- man. J Am Coll Nutr 1994;13:629 - 40.
theless, the nutritional supplement did not impact gonadal [3] Brody S, Preut R, Schommer K, et al. A randomized controlled trial of function, again supporting an adrenal stress mechanism of high dose ascorbic acid for reduction of blood pressure, cortisol, and action. Obviously, in such a multivariate environment, subjective responses to psychological stress. Psychopharmacology cortisol is but one factor in the mechanisms involved in [4] Marsit JL, Conely MS, Stone MH, et al. Effects of ascorbic acid on the repair and remodeling physiological process.
serum cortisol and the testosterone: cortisol ratio in junior elite The Cortitrol and placebo conditions showed similar GH weightlifters. J Strength Cond Res 1998;12:179 - 84.
responses after exercise (despite a dramatic [5] Rodriguez-Martinez MA, Garcia-Cohen EC. Role of Ca(2+) and decrease in plasma cortisol responses to the exercise and vitamin D in the prevention and treatment of osteoporosis. Pharmacol early recovery. Although beyond the scope of this study, [6] Manelli F, Giustina A. Glucocorticoid-induced osteoporosis. Trends future novel investigations are needed to determine if another aggregate or molecular variant of GH beyond the [7] Cernak I, Savic V, Kotur J, et al. Alterations in magnesium and one that is typically measured using various immunoassays oxidative status during chronic emotional stress. Magnes Res (22 kDa) is affected by cortisol. Supporting such research, Hymer et al demonstrated that different sizes of GH and [8] Tsai TH, Lee TF, Chen CF, et al. Modulatory effects of magnolol on potassium-stimulated 5-hydroxytryptamine release from rat cortical GH aggregates exist in different GH-producing cells. Band and hippocampal slices. Neurosci Lett 1995;186:49 - 52.
1 cells (pituitary cells with a density of b1.071 g/cm3) [9] Murphy DL. Neuropsychiatric disorders and the multiple human brain produce and secrete more 22-kDa GH than band 2 cells serotonin receptor subtypes and subsystems. Neuropsychopharmacol- (density N1.071 g/cm3), which produce more GH aggre- gates. They showed that hydrocortisone treatment of [10] Kamath AB, Wang L, Das H, et al. Antigens in tea-beverage prime human Vgamma 2Vdelta 2 T cells in vitro and in vivo for memory band 1 and band 2 pituitary cells was most detrimental to and nonmemory antibacterial cytokine responses. Proc Natl Acad Sci GH formation in band 2 cells, thus impacting higher molecular weight GH aggregates and binding proteins.
[11] Kobayashi K, Nagato Y, Aoi N, et al. Effects of l-theanine on the Thus, future studies are needed to understand cortisol’s release of a-brain waves in human volunteers. Nippon Noegi influence on other forms or aggregates of GH and their [12] Kakuda T, Nozawa A, Unno T, et al. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol The results of this study imply that long-term supple- mentation with Cortitrol may have a favorable impact on [13] Wu H, Lien EJ, Lien LL. Chemical and pharmacological investigations chronic cortisol levels. Thus, the potential exists for of Epimedium species: a survey. Prog Drug Res 2003;60:1 - 57.
improved muscular adaptation to resistance training, in- [14] Monteleone P, Beinat L, Tanzillo C, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans.
creased bone mineral density, and enhanced immune cell function. However, this study is limited in that it examined [15] Monteleone P, Maj M, Beinat L, et al. Blunting by chronic only acute responses to Cortitrol supplementation. Future phosphatidylserine administration of the stress-induced activation studies will need to further examine some of the positive of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Clin adaptations that may occur from chronic reduction in [16] Bouic PJ, Clark A, Lamprecht J, et al. The effects of B-sitosterol cortisol concentrations after Cortitrol supplementation.
(BSS) and B-sitosterol glucoside (BSSG) mixture on selected immune In conclusion, we investigated the impact of Cortitrol parameters of marathon runners: inhibition of post marathon immune supplementation on serum cortisol responses to intense suppression and inflammation. Int J Sports Med 1999;20:258 - 62.
physical stress via acute resistance exercise. We found that [17] Kraemer WJ, Patton JF, Gordon SE, et al. Compatibility of high- Cortitrol attenuated mean cortisol concentrations throughout intensity strength and endurance training on hormonal and skeletalmuscle adaptations. J Appl Physiol 1995;78:976 - 89.
a 95-minute period during a day of rest, and during the pre- [18] Kraemer WJ, Volek JS, Bush JA, et al. Hormonal responses to resistance exercise and early exercise recovery periods.
consecutive days of heavy-resistance exercise with or without These results give validity to the formulation of Cortitrol as nutritional supplementation. J Appl Physiol 1998;85:1544 - 55.
W.J. Kraemer et al. / Metabolism Clinical and Experimental 54 (2005) 657 – 668 [19] Suay F, Salvador A, Gonzalez-Bono E, et al. Effects of competition [30] Tharion WJ, Rausch TM, Harman EA, et al. Effects of different and its outcome on serum testosterone, cortisol and prolactin.
resistance exercise protocols on mood states. J Appl Sport Sci Res Psychoneuroendocrinology 1999;24:551 - 66.
[20] Kraemer WJ, Fry AC. Strength testing: Development and evaluation [31] Wang Y, Li CY, Lin IH, et al. Synthesis and radical scavenging of of methodology. In: Maud P, Foster C, editors. Physiological novel magnolol derivatives. J Pharm Pharmacol 2002;54:1697 - 703.
assessment of human fitness. Champaign (Ill)7 Human Kinetics [32] Yoshida Y, Niki E. Antioxidant effects of phytosterol and its components. J Nutr Sci Vitaminol (Tokyo) 2003;49:277 - 80.
[21] Kraemer WJ, Marchitelli L, Gordon SE, et al. Hormonal and growth [33] Alessio HM, Goldfarb AH, Cao G. Exercise-induced oxidative stress factor responses to heavy resistance exercise protocols. J Appl Physiol before and after vitamin C supplementation. Int J Sport Nutr 1997;7: [22] Follenius M, Brandenberger G, Hietter B. Diurnal cortisol peaks [34] Huang HY, Appel LJ, Croft KD, et al. Effects of vitamin C and and their relationships to meals. J Clin Endocrinol Metab 1982;55: vitamin E on in vivo lipid peroxidation, results of a randomized controlled trial. Am J Clin Nutr 2002;76:549 - 55.
[23] Knoll E, Muller FW, Ratge D, et al. Influence of food intake on [35] Vasankari T, Kujala U, Sarna S, et al. Effects of ascorbic acid and concentrations of plasma catecholamines and cortisol. J Clin Chem carbohydrate ingestion on exercise induced oxidative stress. J Sports [24] McBride JM, Kraemer WJ, Triplett-McBride T, et al. Effect of [36] Thompson D, Williams C, McGregor SJ, et al. Prolonged vitamin C resistance exercise on free radical production. Med Sci Sports Exerc supplementation and recovery from demanding exercise. Int J Sport [25] Wong SH, Knight JA, Hopfer SM, et al. Lipoperoxides in [37] Flerov MA, Gerasimova IA, Rakitskaya VV. Lipid peroxidation in the plasma as measured by liquid-chromatographic separation of striatum of rats during stress after administration of cortisol. Neurosci malondialdehyde-thiobarbituric acid adduct. Clin Chem 1987;33: [38] Kraemer WJ, Noble BJ, Clark MJ, et al. Physiologic responses to [26] Dill DB, Costill DL. Calculation of percentage changes in volumes of heavy-resistance exercise with very short rest periods. Int J Sports blood, plasma, and red cells in dehydration. J Appl Physiol 1974;37: [39] Bush JA, Kraemer WJ, Mastro AM, et al. Exercise and recovery [27] Staron RS, Karapondo DL, Kraemer WJ, et al. Skeletal muscle responses of adrenal medullary neurohormones to heavy resistance adaptations during the early phase of heavy-resistance training in men exercise. Med Sci Sports Exerc 1999;31:554 - 9.
and women. J Appl Physiol 1994;76(3):1247 - 55.
[40] Alen M, Pakarinen A, Hakkinen K, et al. Responses of serum [28] Peake JM. Vitamin C: effects of exercise and requirements with androgenic-anabolic and catabolic hormones to prolonged strength training. Int J Sport Nutr Exerc Metab 2003;13:125 - 51.
training. Int J Sports Med 1988;9:229 - 33.
[29] Li CY, Wang Y, Hu MK. Allylmagnolol, a novel magnolol [41] Hymer WC, Grindeland RE, Salada T, et al. Experimental modifica- derivative as potent antioxidant. Bioorg Med Chem 2003;11: tion of rat pituitary growth hormone cell function during and after spaceflight. J Appl Physiol 1996;80:955 - 70.

Source: http://webupload.dl.cdn.cloudn.co.kr/images/datacenter/book/FORM23_1.pdf