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ORIGINAL RESEARCH
Three Weeks of Creatine Monohydrate Supplementation
Affects Dihydrotestosterone to Testosterone Ratio in
College-Aged Rugby Players
Johann van der Merwe, MBChB, Naomi E. Brooks, PhD, and Kathryn H. Myburgh, PhD
Objective: This study investigated resting concentrations of selected
androgens after 3 weeks of creatine supplementation in male rugby
players. It was hypothesized that the ratio of dihydrotestosterone (DHT,
a biologically more active androgen) to testosterone (T) would change
with creatine supplementation.
Design: Double-blind placebo-controlled crossover study with a
6-week washout period.
Setting: Rugby Institute in South Africa.
Participants: College-aged rugby players (n = 20) volunteered for
the study, which took place during the competitive season.
Interventions: Subjects loaded with creatine (25 g/day creatine
with 25 g/day glucose) or placebo (50 g/day glucose) for 7 days
followed by 14 days of maintenance (5 g/day creatine with 25 g/day
glucose or 30 g/day glucose placebo).
Main Outcome Measures: Serum T and DHT were measured and
ratio calculated at baseline and after 7 days and 21 days of creatine
supplementation (or placebo). Body composition measurements were
taken at each time point.
Results: After 7 days of creatine loading, or a further 14 days of
creatine maintenance dose, serum T levels did not change. However,
levels of DHT increased by 56% after 7 days of creatine loading and
remained 40% above baseline after 14 days maintenance (P,0.001).
The ratio of DHT:T also increased by 36% after 7 days creatine
supplementation and remained elevated by 22% after the maintenance
dose (P,0.01).
Conclusions: Creatine supplementation may, in part, act through an
increased rate of conversion of T to DHT. Further investigation is
warranted as a result of the high frequency of individuals using
creatine supplementation and the long-term safety of alterations in
circulating androgen composition.
Statement of Clinical Relevance: Although creatine is a widely
used ergogenic aid, the mechanisms of action are incompletely
understood, particularly in relation to dihydrotestosterone, and
therefore the long-term clinical safety cannot be guaranteed.
Key Words: creatine supplementation, rugby player, athlete, clinical
safety, DHT:T ratio
(Clin J Sport Med 2009;19:399–404)
INTRODUCTION
Creatine supplementation is a popular ergogenic aid. It
has been extensively researched in various athletic popula-
tions
1
and diseased populations.
2
Loading doses of creatine
taken for 5 to 7 days improves some types of exercise
performance
3–5
and, in some studies, also increased muscle
strength despite the short duration of supplementation.
6,7
Creatine supplementation alone or as part of a multicomponent
putative ergogenic aid may increase muscle mass, particularly
if taken for a longer time period and in conjunction with
increased volume of resistance training.
8
However, although
creatine is a popular ergogenic and androgenic aid used by
professional and recreational athletes, the mechanisms un-
derlying the enhancement of performance and muscle building
by creatine supplementation remain to be clearly elucidated. In
addition, very few studies have investigated the clinical safety
of creatine supplementation. Most studies investigating possi-
ble side effects have focused on renal function and hepatic
markers
9
and, although they have not shown any serious side
effects of creatine supplementation, the studies have been of
short duration
10
and long-term safety is not guaranteed.
11
Two main approaches have been followed to investigate
mechanisms by which creatine may influence skeletal muscle.
One involves the investigation of skeletal muscle biopsies
and the other main approach involves investigating possible
effects of creatine supplementation on the humoral endocrine
response to exercise. Testosterone can stimulate muscle
growth by increasing protein synthesis and potentially reusing
amino acids from muscle protein breakdown.
12
Testosterone,
growth hormone, and insulin growth factor-1 have been shown
to increase as an acute effect of resistance exercise,
13
an effect
that was enhanced by 7 days prior ingestion of a supplement
containing creatine (Muscle Fuel: Advocare, Carollton, Texas).
However, a similar study found no enhancement of the
growth hormone response to a 60-minute bout of resistance
training in subjects who had ingested creatine for 5 days, and
the testosterone response to exercise was not significant, with
Submitted for publication February 1, 2009; accepted July 22, 2009.
From the Department of Physiological Sciences, Stellenbosch University,
Stellenbosch, South Africa.
Reprints: Kathryn H. Myburgh, PhD, Department of Physiological Sciences,
Stellenbosch University, Private Bag XI, Matieland 7602, Stellenbosch,
South Africa (e-mail: khm@sun.ac.za).
Copyright Ó2009 by Lippincott Williams & Wilkins
Clin J Sport Med Volume 19, Number 5, September 2009 www.cjsportmed.com |399
or without the creatine supplementation.
14
In extreme,
overreaching training involving resistance training, it has
even been shown that total testosterone levels decrease after 4
weeks despite creatine supplementation.
15
These studies sug-
gest that the possible role for testosterone as a mediator of the
observed effects of creatine on muscle mass is controversial.
Testosterone can be converted into a more bioactive
metabolite, dihydrotestosterone (DHT), by 5-alpha reductase.
The role of 5-alpha-reductase in testosterone conversion is
well known in the literature focusing on alopecia
16
and prostate
hypertrophy,
17
even in young males with male pattern baldness.
8
In addition, biochemical studies of androgen receptor affinity
indicates that DHT is 4 times more biologically potent than T.
19
Therefore, to further explore this as a potential
mechanism for the effect of creatine supplementation on
muscle, we chose to investigate the ratio of DHT:testosterone
in young male athletes participating in team sports requiring
substantial strength (rugby). Previous studies have mainly
focused on the effects of training combined with creatine
supplementation during the strength improvement phase in
American football players.
20
We chose to investigate the rugby
players during the competitive season to minimize the
potential compounding effect of changing training at the
same time as providing the supplement.
The study design was a double-blind, placebo-controlled
crossover study with a 6-week washout period. We measured
serum testosterone (T) and DHT and calculated the ratio after
21 days of creatine supplementation. We hypothesized that we
would observe a change in the ratio of DHT:T.
METHODS
Subjects
Twenty white males (aged 18–19 years) from a Rugby
Institute situated near Stellenbosch University in South Africa
took part in the study. The study was approved by the
Stellenbosch University Ethics Committee and informed
consent was provided by each subject. None of the subjects
had taken any supplements with their normal diet for 6 weeks
before the study. Subjects were randomized into 2 groups for
a double-blind, placebo-controlled crossover study design with
a 6-week washout period (Figure 1). The randomization was
done as follows: when subjects were handed informed consent
forms, they were assigned a number based on arrival. The even
numbers were assigned to one group and the odd numbers the
other group. There were 4 subjects who dropped out, 2 from
each group. Two subjects left town, 1 subject went overseas
and 1 subject broke a leg. The data from the dropout subjects
were not included in the analysis.
Procedures
Subjects underwent a 7-day loading period with creatine
supplementation or placebo followed by a 14-day maintenance
dose (creatine or placebo). Creatine monohydrate was given
with glucose (25 g/day creatine and 25 g/day glucose) for
a loading dose and 5 g/day creatine and 25 g/day glucose for
a maintenance dose. The placebo group received glucose only
(50 g/day glucose) for a loading dose and 30 g/day glucose for
a maintenance dose. To maintain the double-blind status, the
FIGURE 1. Flow chart of double-blind
crossover study design of participa-
tion of subjects in the study is shown.
400 |www.cjsportmed.com q2009 Lippincott Williams & Wilkins
Merwe et al Clin J Sport Med Volume 19, Number 5, September 2009
supplement and placebo were given as capsules. Both groups
received the same number of capsules during the loading and
maintenance doses.
Training and Dietary Intake
Subjects were part of the Rugby Institute and underwent
standardized training, albeit for different player positions,
during the study. All subjects were residents at the Institute and
the same diet was given to all subjects. During part of the
washout period, all subjects had a short winter break and did
only maintenance training. Therefore, at the beginning of the
second phase of the study, subjects were in similar condition as
the start of the study and not fatigued from consecutive weeks
of match play.
Outcome Measures
Anthropometry measurements were taken on Day 0,
Day 7, and Day 21 in each leg of the study. Six skin fold
measurements were taken (triceps, subscapula, suprailiac,
abdominal, thigh, and midcalf). The average of 2 measure-
ments was calculated and the sum of 6 measurements was used
for calculation of body density and percent body fat.
21
Blood samples were taken at Day 0, Day 7, and Day 21
with athletes in the fully rested condition pretraining. Samples
were taken from the antecubital vein (SST; Vacutainer, BD,
South Africa), left to clot, and placed on ice. Serum was
separated by centrifuging at 3000 rpm at 4°C and samples
were stored at –70°C. All samples were taken at the same time
of day (4:00 PM to 5:00 PM). Serum was separated and frozen
within 1 hour of collection. Testosterone and DHT were
measured using DSL Testosterone and Dihydrotestosterone
radio immunoassay kits (DSL 4000 and DSL 9600; Diagnostic
Systems Laboratories, Inc, Webster, Texas). Analysis was
conducted according to the radioimmunoassay kit instructions.
Mean values for T levels were calculated and compared with
standards of known quantity representing 0 to 86.75 nmol/L
and compared against control values. Study values fall within
the expected range of 10.06 to 34.35 nmol/L for young adult
males. DHT analysis first included an extraction procedure
to remove T and therefore preventing crossreactivity and
rendering the kit 100% specific to DHT. Mean values of DHT
were calculated and compared with standards ranging from
0 to 8.6 nmol/L and controls ranging from 0.433 to 2.012
nmol/L. The laboratory upper limit for coefficient of variation
for both assays was less than 5% for individual subjects’
samples analyzed in triplicate.
Statistical Analysis
Subjects were assigned a number to maintain confiden-
tiality of results. Subjects were randomized into 2 groups at
baseline and baseline characteristics were compared using
Student unpaired ttest. Data collected over the 2 legs of the
study were pooled so that each subject served as their own
control and analyzed using repeated measures analysis of
variance. Differences at each time interval were analyzed post
hoc by Tukey test with significance set at P,0.01.
RESULTS
Baseline Characteristics and Anthropometry
Subjects were aged 18.7 60.53 years and their height
was 1.81 60.05 m. Body mass ranged from 74.4 to 107 kg.
There were no significant differences in any measurements at
baseline between the subjects randomized to placebo first
compared with those randomized to creatine first. As a result
of the crossover nature of the study design, each subject had 2
baseline time points. Baseline 1 was before any supplemen-
tation or placebo and baseline 2 after the 6-week washout
period. After washout, subjects had a similar baseline for
percent body fat and fat-free mass. Therefore, data are
presented as creatine or placebo with results pooled regardless
of which supplement was taken first. The pooled baseline data
is called Day 0.
Anthropometry measurements did not differ between the
two groups on Day 0 (Table 1), and neither creatine loading or
placebo affected body mass, percentage body fat, or fat-free
mass after 7 days or after 21 days.
Blood Measurements
Testosterone levels did not change significantly over
time in either group (P= 0.19; Table 2). With creatine, no
statistically significant increases in T concentrations were seen
after 7 days or after 21 days, but there was more variation in the
means over time (Table 2). Dihydrotestosterone did not change
with placebo; however, in the creatine group, there were sig-
nificant increases in DHT concentrations over time resulting in
a time 3group interaction (time 3group P,0.00001). After
7 days of loading, the increase in DHT was 56%, and after 14
more days on the maintenance dose, the elevation was still
40% above baseline.
After calculating the ratio of DHT to T, it was found that
there was a significantly higher ratio in the creatine group
(group 3time P,0.00001). This change in ratio amounted to
a 36% increase in conversion of T to DHT after 7 days of
TABLE 1. Body Composition Before Supplementation
(Day 0), After Loading (Day 7), and After Maintenance
Doses (Day 21) of Creatine with Carbohydrate or
Placebo with Carbohydrate
Day 0 Day 7 Day 21
Body mass, kg
Placebo 86.80 69.90 87.30 610.1 87.26 69.96
Creatine 87.04 610.66 87.80 610.88 87.80 610.82
Sum of 6 skin
folds, mm
Placebo 274 658 274 655 272 656
Creatine 272 654 269 649 269 643
Percent body fat
Placebo 13.53 63.95 13.54 63.94 13.47 63.97
Creatine 13.43 63.92 13.36 64.02 13.30 63.95
Fat-free mass, kg
Placebo 75.0 65.7 75.0 65.8 75.0 65.8
Creatine 75.0 66.7 75.8 66.8 75.8 66.5
Values are mean 6standard deviation; n = 20 subjects completing each of the arms
of the crossover design.
q2009 Lippincott Williams & Wilkins www.cjsportmed.com |401
Clin J Sport Med Volume 19, Number 5, September 2009 Creatine Supplementation and DHT:T Ratio in Male Rugby Players
creatine supplementation (post hoc test: P,0.001). The
conversion was still elevated by 22% at 21 days after 14 days
on maintenance (post hoc test: P,0.01).
DISCUSSION
Important features of this study were that all athletes
were in peak competitive condition at baseline and were
involved in the same training and competition structures.
Similar to Ziegenfuss et al,
22
the current study had a relatively
long washout period of 6 weeks as opposed to more commonly
used 4-week washout.
23–25
The main finding that is discussed
subsequently is that this is the first study to report an increase
in the DHT to T ratio in response to creatine loading, a
response that was also maintained during the maintenance
phase for at least another 2 weeks in young trained athletes. In
addition, this study used creatine monohydrate with carbohy-
drate as opposed to a multicomponent supplement so that all
findings can be attributed to creatine only.
Several other studies have investigated the possibility
that changes in androgens may underlie the positive effects of
creatine supplementation on muscle mass with creatine taken
alone or with other components. These studies investigated
mainly the growth hormone and insulin-like growth factor-1
axis or testosterone and sex hormone-binding globulin, or all,
but not DHT.
13,15
In 2 studies, increased growth hormone
and T responses were seen immediately after exercise in
supplemented subjects, who were supplemented with creatine
combined with branch-chain amino acids, taurine, caffeine,
and glucouronolactone.
26,27
In the first study, the supple-
mented subjects completed a loading dose phase. Although
subjects taking placebo also experienced a postexercise
increase in growth hormone, this increase was significantly
greater in the supplemented group than the control group.
29
In
the second study, the same research group found increases in
T and growth hormone after exercise in both groups when
supplementation was acute.
27
In these studies, the duration of
supplementation was 1 week
26
or 1 dose,
27
which raises the
question of whether or not a longer exposure would have
resulted in different results. Indeed, increased levels of T were
found in resting blood samples after 10 weeks of resistance
training with creatine supplementation compared with placebo
and with creatine and beta-alanine supplementation.
28
Similar
to Op’t Eijnde and Hespel, we did not find an effect of sup-
plementation with only creatine on resting testosterone levels
in trained subjects
14
despite the loading phase of 7 days and
a maintenance phase of another 14 days. Also, no changes in
plasma T were found after 6 weeks of supplementation with
beta-hydroxy beta-methylbutarate or the combination of crea-
tine and hydroxy beta-methylbutarate.
29
Therefore, our results
agree with these studies as well as Kraemer et al.
13
However,
the latter study did find a greater T response to a resistance
exercise training bout after a multicomponent supplement
containing 3 g creatine.
On the other hand, Volek et al
15
even found declines in
resting T despite creatine supplementation in subjects who
were becoming overreached. The players in our study did not
become overreached despite the long duration of the study and
competitive season, because there was a 2-week midseason
break, which coincided with the first 2 weeks of washout. Both
of these studies used creatine monohydrate as a single putative
ergogenic substance. In our study, creatine was taken in con-
junction with carbohydrate to enhance muscle uptake of
creatine but was not taken in combination with any other
putative anabolic supplements such as those that may be
hypothesized to work synergistically.
With no effect on resting T levels, the effect of creatine
supplementation on DHT becomes an even more important
finding. This effect was a large increase in DHT rather than
a marginal (possibly physiologically insignificant) effect.
As mentioned earlier, 5-alpha-reductase converts tes-
tosterone to DHT. There is low
30
or no
31
5-alpha-reductase in
muscle or bone suggesting that any potential effect on muscle
is mediated by conversion at other sites. Comparing the
androgen receptor physiology of T and DHT, studies have
indicated that DHT has higher affinity as well as longer recep-
tor occupancy than T, rendering it a more potent androgen.
19,32
In the face of T deficiency, DHT alone or DHTand T have been
used to prevent muscle weakness and atrophy.
33
However,
mechanistic studies do not clearly indicate its effect on muscle
tissue; DHT treatment in orchidectomized rats did not activate
the Akt anabolic signaling pathway involved in muscle
hypertrophy.
34
Nevertheless, in tissue culture addition of DHT
to the culture media, stimulate C2C12 cells (a satellite cell
line), proliferated
35
and promoted the commitment of a
pluripotent cell line to myogenic differentiation.
36
The second major finding of the current study was
a higher DHT:T ratio after 7 days of creatine loading, which
was maintained with another 2 weeks of maintenance dose.
Clinically, an increased ratio of DHT:T has been linked to
higher male pattern baldness.
16
Therefore, it is important to
also investigate the effects of this ratio on target tissues.
Litman et al
37
found racial/ethnical differences in the
ratio of DHT:T. They purported that prostate cancer, body
composition, and bone mass differences between the ethnic/
racial groups may be explained by differences in this ratio. In
this context, it is also pertinent to discuss the physiology of
TABLE 2. Testosterone, Dihydrotestosterone, and
Dihydrotestosterone to Testosterone Ratio Before, After
Loading, and After Maintenance Doses of Creatine with
Carbohydrate or Placebo with Carbohydrate
Day 0 Day 7 Day 21
Testosterone
(T; nmol/L)
Placebo 17.09 63.42 17.02 64.11 17.04 65.25
Creatine 14.44 62.95 16.08 62.86 16.69 64.61
Dihydrotestosterone
(DHT; nmol/L)
Placebo 1.26 60.52 1.09 60.40 1.06 60.43
Creatine 0.98 60.37 1.53 60.50* 1.38 60.45*
DHT:T ratio
Placebo 0.074 60.027 0.066 60.022 0.064 60.023
Creatine 0.069 60.023 0.096 60.031* 0.086 60.032†
Values are mean 6standard deviation; n = 20 subjects completing each of the arms
of the crossover design.
*P,0.001.
†P,0.01.
402 |www.cjsportmed.com q2009 Lippincott Williams & Wilkins
Merwe et al Clin J Sport Med Volume 19, Number 5, September 2009
DHT and DHT:T ratio without reference to possible ergogenic
mechanisms, but rather focusing on clinical safety. Previous
studies addressing safety issues indicated that creatine
supplementation does not seem to have short-term negative
effects on renal or hepatic function.
9
Nonetheless, more
comprehensive studies of long-term safety are still required.
11
The prostate is the best known tissue that is highly responsive
to androgens, including DHT.
33
DHT may be associated with
benign prostate hypertrophy,
39
but the association with
prostate cancer remains controversial.
40,41
Given this discussion, it would seem that DHT or the
DHT:T ratio may well be possible mechanisms for positive
effects of creatine on muscle mass. The increase in DHT and
DHT:T ratio after 7 days of creatine loading was not seen at
Day 21. There may be a dose–response to the amount of
creatine ingested and the maintenance dose may not be high
enough to maintain the increased ratio. However, in the current
study, we did not see changes in body mass or percent body
fat. Our study recruited rugby players during their competitive
season, after their initial preseason strength orientated training
was completed. On the one hand, this enabled us to determine
the effects of creatine supplementation on already trained
individuals without major additional training changes.
However, this may explain why body composition did not
change. One could speculate that a supplementation period of
longer than 21 days may have altered body composition even
in these subjects whose training did not change appreciably
during the course of the study.
In conclusion, creatine supplementation may act, at least
in part, through the increased rate of conversion of T to DHT.
Because of the potential clinical relevance of the endocrine
results of this study and the high frequency of individuals
using creatine supplementation without monitoring, further
investigation is warranted. Clearly, future studies on the
putative anabolic effects of creatine supplementation should be
more comprehensive in terms of potential humoral and
intramuscular effects.
ACKNOWLEDGMENTS
We thank the rugby players for their cooperation
throughout the duration of the study. We also thank the staff
involved with the rugby players and the Institute for
accommodating the study. Thanks to Mrs. Gail Nell (Chemical
Pathology, Grootte Schuur Hospital), Anneke Le Roux
(Biokineticist, private practice), and Jacolene Kroff, PhD
(Sport Science, Stellenbosch University) for technical support.
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