Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy

Abstract

The creatine/phosphocreatine/creatine kinase circuit is instrumental in regulating high-energy phosphate metabolism, and the maintenance of cellular energy turnover. The mechanisms by which creatine is able to buffer and regulate cellular energy balance, maintain acid-base balance, and reduce the effects of oxidative stress have led to a large number of studies into the use of creatine supplementation in exercise performance and to treat diseases associated with cellular energy depletion. Some of these studies have identified sex-specific responses to creatine supplementation, as such; there is the perception, that females might be less receptive to the benefits of creatine supplementation and therapy, compared to males. This review will describe the differences in male and female physique and physiology that may account for such differences, and discuss the apparent endocrine modulation of creatine metabolism in females. Hormone-driven changes to endogenous creatine synthesis, creatine transport and creatine kinase expression suggest that significant changes in this cellular energy circuit occur during specific stages of a female's reproductive life, including pregnancy and menopause. Recent studies suggest that creatine supplementation may be highly beneficial for women under certain conditions, such as depression. A greater understanding of these pathways, and the consequences of alterations to creatine bioavailability in females are needed to ensure that creatine is used to full advantage as a dietary supplement to optimize and enhance health outcomes for women.

Full text

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DOI 10.1007/s00726-016-2199-y
Amino Acids
REVIEW ARTICLE
Creatine for women: a review of the relationship between creatine
and the reproductive cycle and female‑specific benefits of creatine
therapy
Stacey J. Ellery1 · David W. Walker1 · Hayley Dickinson1
Received: 19 November 2015 / Accepted: 8 February 2016
© Springer-Verlag Wien 2016
that creatine is used to full advantage as a dietary supple-
ment to optimize and enhance health outcomes for women.
Keywords Women’s health · Nutrition · Reproduction
Introduction
The creatine/phosphocreatine/creatine kinase circuit is inte-
gral to the maintenance of cellular energy (ATP) turnover,
and thus cellular function (Wallimann et al. 2007), and it
has particular importance in tissues with high and fluctuat-
ing energy demands, such as skeletal muscle, cardiac mus-
cle and the brain (Wallimann et al. 1992). Creatine (Cr)
is readily obtained from a diet containing meat and fish,
and is also synthesized endogenously by the body, via a
two-step enzymatic reaction that consumes arginine, gly-
cine and methionine (Brosnan and Brosnan 2007). Once
absorbed or synthesized, creatine is released into the circu-
lation and actively transported into tissues by the Creatine
Transporter 1 (CrT1), encoded by the SLC6A8 gene (Guim-
bal and Kilimann 1993). Within the cell ~75 % of creatine
is phosphorylated via creatine kinase to produce phospho-
creatine (PCr), which then acts as a phosphate donor for the
regeneration of ATP from ADP.
The phosphagen system provides support to mitochon-
drial oxidative phosphorylation and cellular ATP turno-
ver by mitigating temporal and spatial imbalances in ATP
supply and demand (Ellington 1989). The creatine/phos-
phocreatine/creatine kinase circuit is also tightly coupled
with mitochondrial structure and bioenergetics (Guidi
et al. 2008), and the activity of this biochemical reaction
has a mild antioxidant effect because the rephosphorylation
of ADP via PCr consumes a proton (H+). These proper-
ties give the creatine/phosphocreatine reaction the ability
Abstract The creatine/phosphocreatine/creatine kinase
circuit is instrumental in regulating high-energy phosphate
metabolism, and the maintenance of cellular energy turn-
over. The mechanisms by which creatine is able to buffer
and regulate cellular energy balance, maintain acid–base
balance, and reduce the effects of oxidative stress have led
to a large number of studies into the use of creatine sup-
plementation in exercise performance and to treat diseases
associated with cellular energy depletion. Some of these
studies have identified sex-specific responses to creatine
supplementation, as such; there is the perception, that
females might be less receptive to the benefits of creatine
supplementation and therapy, compared to males. This
review will describe the differences in male and female
physique and physiology that may account for such differ-
ences, and discuss the apparent endocrine modulation of
creatine metabolism in females. Hormone-driven changes
to endogenous creatine synthesis, creatine transport and
creatine kinase expression suggest that significant changes
in this cellular energy circuit occur during specific stages
of a female’s reproductive life, including pregnancy and
menopause. Recent studies suggest that creatine supple-
mentation may be highly beneficial for women under cer-
tain conditions, such as depression. A greater understand-
ing of these pathways, and the consequences of alterations
to creatine bioavailability in females are needed to ensure
Handling Editor: T. Wallimann and R. Harris.
* Hayley Dickinson
hayley.dickinson@hudson.org.au
1 Hudson Institute of Medical Research and Department
of Obstetrics and Gynaecology, The Ritchie Centre, Monash
Medical Centre, Monash University, 27-31 Wright St.,
Clayton, Melbourne 3168, Australia

S. J. Ellery et al.
1 3
to buffer the pH of the cytosol, thus protecting cells from
damage associated with internal acidification and ATP
depletion (Sestili et al. 2011).
Vertebrates express four different creatine kinase (CK)
isoforms, and it is generally the expression pattern of these
isoforms that govern the way in which creatine is used by
a cell (Eppenberger et al. 1964, 1967; Dawson et al. 1967;
Patra et al. 2012). Muscle creatine kinase (MCK) is a cyto-
solic isoform of CK expressed solely in sarcomeric skeletal
and cardiac muscle cells (Turner et al. 1973; Wallimann
et al. 1977). All other non-muscle cells, including the kid-
ney, bone and neuronal tissue express the ubiquitous brain
(BCK) isoform of creatine kinase (Wallimann et al. 2011).
In addition to these cytosolic isoforms two mitochondrial
isoforms of creatine kinase, located between the inner
and outer mitochondrial membranes have been character-
ized (Jacobs et al. 1964). Sarcomeric mitochondrial CK
(sMITCK) is expressed alongside MCK in striated skeletal
and cardiac muscle cells, whilst mitochondria of other tis-
sue types express a ubiquitous isoform (uMITCK) along
with BCK (Wyss and Kaddurah-Daouk 2000). Despite var-
iations in location and expression patterns, all CK isoforms
catalyse the reversible transfer of the γ-phosphate group of
ATP to the guanidine group of creatine, to yield PCr and
ADP, and vice versa (Wyss and Kaddurah-Daouk 2000).
Increasing dietary consumption of creatine increases the
intracellular pool of creatine/phosphocreatine available for
ATP re-synthesis and can prolong cellular energy homeo-
stasis. The use of dietary creatine supplementation as an
ergogenic aid for exercise performance, and as a targeted
therapeutic for a wide range of conditions where mitochon-
drial demise and depleted ATP underlie the pathology has
been widely studied (see reviews, Feldman 1999; Gualano
et al. 2010; Wallimann et al. 2011). Despite the fundamen-
tal role this phosphagen circuit plays at a cellular level,
from time-to-time studies into creatine homeostasis and the
benefits of dietary creatine supplementation for exercise
performance and disorders of metabolism have identified
differences in the sex-specific responses to creatine load-
ing, with the benefits for women, particularly in regard to
exercise physiology, being less than those reported for men
(Mihic et al. 2000).
Here we review and discuss the physiological differ-
ences between males and females that may lead to differ-
ences in creatine metabolism between the sexes, with a
focus on how the female utilises creatine under different
physiological conditions, including age, sexual maturity
and pregnancy. We discuss the areas where significant
knowledge gaps exist, and highlight the need to overcome
these to ensure that creatine is an effective ergogenic aid for
female athletes; that creatine supply during pregnancy is
maintained for appropriate fetal growth and development;
and its use as a therapeutic intervention to treat a variety
of diseases or conditions, such as clinical depression and
sarcopenia, that are underpinned by cellular energy failure
are realised.
Comparison of creatine metabolism between men
and women
A number of differences in the storage and utilization of
creatine have been identified between healthy males and
females (Brosnan and Brosnan 2007). These are summa-
rized in Table 1. When assessing creatine synthesis rates in
the population, based on age, females produced amounts of
endogenous creatine that were consistently 70–80 % lower
than males (Brosnan and Brosnan 2007). Dietary intake
of creatine of adult females aged 20–39 is also lower than
their male counterparts (Brosnan and Brosnan 2007). This
lowered rate of synthesis and consumption of creatine is
the likely driver behind the reduced mean excretion rate of
creatinine in females, which is ~80 % of the rate of excre-
tion in males (Cockcroft and Gault 1976).
Table 1 Summary of reported differences in creatine metabolism between men and women
Adult male Adult female Source
Circulating creatine
Circulating Guanidinoacetate (GAA) 3.12 ± 0.66 μmol/l 2.02 ± 0.54 μmol/l Kalhan et al. (2015)
Creatine synthesis 3.7–7.7 mmol day−12.6–6.2 mmol day−1Brosnan and Brosnan (2007)
Serum creatine 40.8 ± 19.0 μmol/l 50.2 ± 20.6 μmol/l Delanghe et al. (1989)
Creatinine clearance 1.0 0.75 Cockcroft and Gault (1976)
Dietary intake
Daily meat consumption 146 g 107 g Delanghe et al. (1989)
Daily creatine intake 7.9 mmol/day 5.0 mmol/day Brosnan and Brosnan (2007)
Physique
Skeletal muscle mass 33 kg 21 kg Janssen et al. (2000)
Muscle Creatine content (vastus lateralis) 132 ± 10 mmol/kg 145 ± 10 mmol/kg Forsberg et al. (1991)

Creatine for women: a review of the relationship between creatine and the reproductive cycle…
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As skeletal muscle is the major storage compartment of
creatine in the human body variation in the physical make
up of men and women may be a major determinant of the
difference of creatine homeostasis between the sexes. Jans-
sen et al. (2000) measured skeletal muscle mass and distri-
bution between 468 healthy adult males and females, and
reported that males had significantly more skeletal muscle,
both in terms of total mass (33 kg for men and 21 kg for
women) and percentage body composition (38.4 % mens
and 30.6 % for womens) (Janssen et al. 2000). Interest-
ingly, in a study where biopsies of the vastus lateralis mus-
cle were assessed for creatine content, females appeared to
store about 10 % more creatine compared to males, relative
to alkali-soluble protein (ASP) (Forsberg et al. 1991). This
finding held irrespective of subject age and could not be
attributed to differences in the proportion of fast and slow
twitch fibre types or fibre cross sectional area. The higher
percentage of stored creatine in female skeletal muscle,
but the larger mass of skeletal muscle in men may account
for the fact that on a standard western diet, which includes
animal products, and where females consume around 25 %
less meat than males, serum creatine levels are relatively
similar between the sexes (Delanghe et al. 1989). A recent
comparison between males and females showed that base-
line guanidinoacetate (GAA) levels were lower in women
than men and directly correlated with muscle mass; abso-
lute synthesis rate of creatine was less in females than
males; and after a 5-day creatine loading regime, women
gained weight and men did not (Kalhan et al. 2015). The
authors concluded that the increased body weight of female
subjects was likely due to water retention (Powers et al.
2003) and did not report any other physiological variables
associated with fluid retention, such as changes in blood
pressure or renal function.
Creatine metabolism and exercise performance
in males and females
Concerns about the ergogenic potential of supplemen-
tary creatine in women have been raised, as a higher rest-
ing total creatine content in skeletal muscle could dimin-
ish the capacity for creatine loading prior to exercise, and
a lower total muscle mass has been correlated to lower
CK activity (Norton et al. 1985; Forsberg et al. 1991). A
study conducted by Mihic et al. (2000) directly assessed
potential sex differences of acute dietary creatine loading
on fat-free mass, blood pressure, plasma creatinine and CK
activity, and concluded that increased creatine consumption
increased total body mass and fat free mass for males and
females, but that the effect was significantly greater in men
(Mihic et al. 2000). In addition, only creatine supplementa-
tion in men has been shown to reduce amino acid oxidation
and protein breakdown following strenuous exercise (Par-
ise et al. 2001). This study concluded that the reasons for
the differences between male and female participants were
unclear, but not likely associated with muscle total creatine
or phosphocreatine concentrations (Parise et al. 2001).
While the consensus of these studies is that the perfor-
mance-enhancing effect of creatine in females is less than
it is in males, they have generally failed to consider the role
of sex hormones and the stage of the menstrual cycle of the
female subjects at the time of the study.
Sex hormone regulation of creatine homeostasis
There is substantial evidence supporting the contention
that estrogens and progesterone influence female skeletal
muscle metabolism (Volek et al. 2006). Under standard
exercise conditions there are significant differences (albeit,
small) in substrate utilization between males and females,
with females favoring lipid metabolism over carbohydrate
metabolism (Braun and Horton 2001). These differences
have been attributed to the expression of female sex hor-
mones, with progesterone down-regulating glucose pro-
duction and estrogens mobilizing lipids, with the overall
effect of shifting metabolism to conserve carbohydrates
(Godsland 1996). The degree of these hormone driven
shifts in female muscle metabolism have been linked to
stages of the menstrual cycle, with affects most prominent
in the luteal phase of the menstrual cycle when the level
of estrogens are at their peak (Volek et al. 2006). Stages
of the menstrual cycle and thus circulating levels of estro-
gens have also been linked to reduced muscle damage after
eccentric exercise through preventing CK release (Williams
et al. 2015). Considering these fundamental shifts associ-
ated with sex hormones for skeletal muscle metabolism, the
roles that estrogens and progesterone have for the overall
storage and metabolism of creatine for women certainly
deserves further study.
Creatine kinase activities, along with expression of key
enzymes for the endogenous synthesis of creatine, are
affected by sex hormones (Wyss and Kaddurah-Daouk
2000). Studies conducted in the rat kidney, testis and
decidua have shown that estrogens, diethylstilbesterol and
testosterone all influence the expression of arginine-gly-
cine aminotransferase (AGAT) (Walker 1979; Hasegawa
et al. 1992). As AGAT is the rate-limiting step of creatine
synthesis, up-regulation of AGAT expression is indicative
of increased de novo creatine synthesis. In the tissues that
express receptors for estrogens or androgen, estradiol and
testosterone have also been shown to stimulate CK activ-
ity (Malnick et al. 1983; Sömjen et al. 1989). Of particu-
lar interest for women is the cyclic nature of sex hormone
regulation. Studies have shown that in the rat, CK activity

S. J. Ellery et al.
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increases and decreases in synchrony with the estrous cycle,
and in relation to increased and decreased production of
estrogens (Sömjen et al. 1991). Whether elevated levels of
serum CK correlate with the endometrial tissue breakdown
that progesterone withdrawal induces during menstruation
is yet to be elucidated, but can not be ruled out as contribu-
tor to these changes (Emera et al. 2012). In terms of the
effectiveness of dietary creatine supplementation either for
athletic performance or for other therapeutic purposes, the
implications of the possible changes in creatine metabo-
lism in line with reproductive status of women has not been
thoroughly investigated. In a study of serum CK levels in
110 school-aged girls, the 21 subjects who were reported as
menstruating on the day that blood was collected for assay
of serum CK levels returned values at the upper end of the
normal range distribution for their age group (46.6 IU/l),
compared to the non-menstruating aged-matched controls
(39.5 IU/l) (Bundey et al. 1979). This study did not take
into consideration the diet, body composition, or exercise
status of the subjects, hence the nature of this relationship
between the menstrual cycle and CK activity still warrants
further investigation.
Female age, sexual maturity and creatine metabolism
Studies conducted through the 1960s and 1970s inves-
tigating the usefulness of serum CK levels as a predictor
of being a carrier of the duchenne muscular dystrophy
(DMD) gene mutation revealed that serum CK levels vary
in women of different ages and sexual maturity. Bun-
dey et al. (1979) examined serum CK levels in women
of different reproductive stages, including pre- and post-
menarche, pregnancy and menopause, and found the high-
est serum CK values were in pre-menarche teenage girls,
and decreased progressively in post-menarche teenagers
and into reproductive maturity. The lowest range of CK
values were present in early pregnancy (16 weeks or less),
when CK values were <50 % of those reported in teenage
girls (Bundey et al. 1979). The relationship between the
different stages of reproductive life and CK levels is not
known. We speculate that age related changes in estrogens
may be associated with these CK levels, however, given the
overwhelming evidence that high CK levels indicate tissue
damage, further work in this area is required to tease out
these associations.
Serum creatine kinase and pregnancy
A study by King et al. (1972) looked more specifically
at serum CK levels across pregnancy. Findings of this
study were consistent with those of Bundey et al. (1979)
described above, in that maternal serum CK decreased
significantly between 8 and 20 weeks of gestation. The
authors discussed the potential role of hemodilution in
these observations, but concluded that the degree of change
was too large to be attributed solely to the normal, preg-
nancy-related increase in maternal blood volume (King
et al. 1972). An earlier study by Konttinen et al. (1963)
described serum CK levels during late pregnancy, delivery
and early postpartum. They found a large range of serum
CK values during late pregnancy (6.04 ± 5.77 IU/ml),
compared to relatively consistent values obtained from
healthy non-pregnant controls (2.1 ± 0.9 IU/ml). Interest-
ingly, the highest CK levels were detected not at delivery,
but a day later (Konttinen and Pyörälä 1963). This finding
was later confirmed in another study of 80 healthy pregnan-
cies where a significant increase in maternal serum CK lev-
els was observed on the first day postpartum (Emery and
Pascasio 1965). Strikingly, values of serum CK detected in
pregnant women at term (Konttinen and Pyörälä 1963) are
comparable to CK values commonly observed following
myocardial infarction (Konttinen and Halonen 1963). This
study also compared the CK levels in three term pregnant
and three non-pregnant uterine muscle samples, to find that
CK levels of pregnant uterine muscle (average, 219,500;
range 199,000–234,500 units/g wet weight) was substan-
tially higher than that of the non-pregnant uterus (average,
16,200; range 13,500–21,500 units/g wet weight) (Kont-
tinen and Pyörälä 1963). It was therefore concluded that the
physical exertion of labor and creatine kinase efflux from
the contracting and then involuting uterus were the major
contributors to the increase in serum CK in women for the
first 1–4 days postpartum. The study of Emery and Pasca-
sio (1965) supported these findings, showing that CK levels
of the pregnant myometrium were significantly higher than
the myometrium of non-pregnant females. This study also
described that there appeared to be a difference (although,
not quite significant) of CK values for the myometrium
directly under the placenta compared to other sites of the
uterus (Emery and Pascasio 1965).
In addition to changes in maternal serum CK lev-
els due to postpartum muscle breakdown, it is also likely
that changes in female sex hormone expression during
pregnancy, labor, delivery, and postpartum contribute sig-
nificantly to changes observed in serum and tissue CK
levels. In addition to estrogens, progesterone has been
linked to CK activity in the myometrium (Lanza 1974).
In non-gravid women injected with various concentrations
of progesterone prior to hysterectomy, CK levels meas-
ured in fundus biopsies were lower than for biopsies from
untreated women; exposure of uterine tissue to 500 mg of
progesterone for 24 h before biopsy was associated with a
decrease of CK levels in the myometrium by ~30 %. Sig-
nificantly, progesterone had no effect on CK levels in the
rectus muscle, indicating a specific effect of progesterone
on CK in uterine muscle fibres (Lanza 1974).

Creatine for women: a review of the relationship between creatine and the reproductive cycle…
1 3
A limitation in evaluating the above studies is that data
collection was usually cross-sectional, and the relative
expression of CK isoforms were not examined in detail.
As many of the studies discussed have used CK as a bio-
marker for other conditions (e.g., serum CK to indicate car-
riers of the gene mutation associated with DMD) there has
been limited discussion of the physiological relevance of
changes to serum CK levels during different phases of the
reproductive cycle. To the knowledge of the authors there
are no studies (in any species) that provide longitudinal
data of changes to serum CK levels over the life course of
male, or female, individuals. With respect to the findings
associated with changes to serum CK levels throughout a
female’s reproductive life, how increased CK levels (serum/
tissue) influence creatine/phosphocreatine utilization; what
increased CK levels tell us about the metabolic demands of
those cells at that particular time; whether these changes
affect creatine synthesis; and what the consequences are
if these shifts do not occur as required, are questions that
should be explored in more detail. Nevertheless, the age
and stage of reproductive cycle of females should be taken
into consideration whenever studies of creatine metabolism
in females are undertaken; as it is clear that creatine kinase
activity (and perhaps creatine metabolism) is intrinsically
connected to changes in the female reproductive cycle.
Creatine metabolism and pregnancy
Is creatine an essential dietary metabolite
of pregnancy?
The link between creatine and the feto-placental unit was
established in 1974, with studies by Miller et al. describ-
ing the active transport of creatine into the human placenta
from the maternal circulation, where it appears to pool and
then diffuse down a concentration gradient into the fetal
circulation (Miller et al. 1974). Similar observations have
also been made in the pregnant rat and spiny mouse (Miller
et al. 1977; Ireland et al. 2008). The potential role of the
placenta in fetal creatine supply from early in gestation is
supported by identification of SLC6A8 mRNA in the human
placenta from 13 weeks gestation (Miller et al. 1974; Nash
et al. 1994). Hormones known to be up-regulated during
pregnancy (IGF-1, triiodothyronine) are known mediators
of increased SLC6A8 expression (Osathanondh et al. 1976;
Furlanetto et al. 1978) and may induce increased expres-
sion of SLC6A8 in the placenta and increase creatine uptake
by virtue of their effects on the Na+ transmembrane poten-
tial, as has been shown for skeletal myoblast cells (Odoom
et al. 1996).
In addition to transfer of creatine from the placenta to
the fetus, the high metabolic activity of the placenta itself
raises questions about its direct requirement for creatine/
phosphocreatine. For the creatine/phosphocreatine/CK
circuit to operate as an effective shuttle of ATP from the
site of synthesis at the mitochondria to areas of demand
in the cytosol, there needs to be coordinated expression of
ubiquitous mitochondrial CK (uMITCK) and ubiquitous
brain-type CK (BCK), as genes for these two isoforms of
CK are located on different chromosomes (Stallings et al.
1988; Haas et al. 1989). Thomure et al. (1996) studied CK
mRNA expression in the human placenta across gestation
and concluded that the expression of uMITCK and BCK
was indeed highly coordinated. Both uMITCK and BCK
were expressed, albeit at low levels in the first and second
trimesters of pregnancy, before a substantial increase in the
expression of both enzymes in the third trimester (Thomure
1996). This pattern of expression parallels the increased
metabolic activity of the placenta in late gestation in the
human and many other species, and suggests that the CK
pathway has an integral role in placental metabolism,
an assumption consistent with the evolutionary develop-
ment of CK in other tissues of high and fluctuating energy
demands, such as skeletal muscle (Thomure 1996; Wyss
and Kaddurah-Daouk 2000). It is likely that rising concen-
trations of serum estrogens during pregnancy may regulate
the increases in both uMITCK and BCK expression across
gestation in the human placenta, as response elements to
estrogens have been identified on both the uMITCK and
BCK genes (Payne et al. 1993).
Whilst not considered an essential metabolite to support
fetal growth and development at this point in time, con-
sideration should be given to the effect that low maternal
creatine levels might have on fetal growth and develop-
ment. Dietary preferences that avoid consumption of ani-
mal products, or variations of the de novo synthesis of cre-
atine in the mother, might affect the provision of creatine to
the fetus and placenta. It is not yet known when the reno-
hepatic axis in the human fetus is developmentally mature
enough to be able to synthesize creatine from arginine, gly-
cine, and methionine, and presumably until this time there
is an absolute requirement for transfer of creatine from
the maternal and placental creatine pools. A study of cre-
atine homeostasis in the pregnant spiny mouse showed that
maternal creatine synthesis, excretion, transport and stor-
age were all fundamentally changed by pregnancy (Ellery
et al. 2015b), suggesting that pregnancy provokes sub-
stantial and far-reaching adaptations to creatine balance in
the mother. These changes include a decrease in maternal
plasma creatine concentration, decreased renal excretion
of creatine between mid and late gestation, increased renal
AGAT mRNA and protein expression, and increased CrT1
mRNA expression in the heart and gastrocnemius muscle
just prior to parturition, raising the possibility that altera-
tions to maternal creatine homeostasis might be a necessary

S. J. Ellery et al.
1 3
adjustment of maternal physiology with pregnancy to meet
the metabolic demands of the placenta and developing fetus
(Ellery et al. 2015b). This notion is also supported by stud-
ies conducted by Braissant et al. (2005), describing embry-
onic expression of AGAT, GAMT and CrT1 in numerous
tissue types in the rat, particularly the central nervous sys-
tem, from early in gestation. This study placed emphasis on
the need for creatine for adequate growth and development
in utero (Braissant et al. 2005). These studies are yet to elu-
cidate whether placental and fetal creatine homeostasis is
different for male and female fetuses. There is increasing
evidence that placental function, especially metabolic func-
tion, is modified by the sex of the fetus (O’Connell et al.
2013). This is an area of research that needs further atten-
tion, and may provide useful insights into the role creatine
might have in obstetric conditions where placental cellular
energy failure may be a factor in major pathologies such as
birth asphyxia, intrauterine growth restriction or stillbirth.
A recent retrospective study in pregnant women identi-
fied changes to creatine homeostasis, in terms of plasma
and urinary creatine concentrations with advancing gesta-
tion (Dickinson et al. unpublished observations). This study
provides data to suggest that plasma and urinary creatine
concentrations are higher in pregnant women compared
to non-pregnant women, and that placental and newborn
weight at birth are related to maternal creatine excretion.
These findings indicate that creatine may be an impor-
tant determinant of fetal growth and development, and
that maintenance of maternal creatine homeostasis across
pregnancy may be vital for the health of the newborn. This
notion is supported by a human study dating back to 1913,
where increases in body weight of a newborn was shown
to be roughly proportional to the creatine excreted in the
urine by the mother (indicative of more than adequate cir-
culating levels of creatine) (Mellanby 1913). Indeed, there
is a great need to know when the human fetus can synthe-
size creatine. While important for understanding in utero
development and placental supply of creatine, the increased
numbers of preterm infants, and their subsequent neuro-
logical decline, raise the possibility that cerebral creatine
deficiency is a consequence of preterm birth not yet fully
recognized, clinically.
It is also of interest to note that, in addition to late gesta-
tional and postpartum pregnant women, newborn babies are
reported to have very high levels of serum CK—up to 10
times higher than normal healthy adult levels (Gilboa and
Swanson 1976). These increased levels begin to decline
by 4 days after birth and reach average population levels
by 6–10 weeks of age. These high serum CK values are
thought to arise from the physical stress placed on the new-
born during labor and delivery (Rudolph and Gross 1966),
although Gilboa et al. (1976) reported that mean CK levels
in the cord blood of babies delivered via caesarean section
were higher than the cord blood levels detected in vaginally
delivered babies (Gilboa and Swanson 1976). Conversely,
mean capillary CK levels were higher in vaginally delivered
newborns compared to caesarean delivered babies. Hence,
there is no clear association with birth trauma and newborn
serum CK levels. Also unique to newborns in the first few
days of life is that venous and capillary levels of CK are
similar, unlike the adult where CK levels are slightly but
significantly lower in capillary compared to venous blood
(Gilboa and Swanson 1976). The physiological significance
of increased serum CK levels in newborns is not known.
Again, as these studies were conducted purely to assess the
potential of CK as a biomarker for DMD, the actual physi-
ological relevance of serum CK levels in the newborn has
not been thoroughly investigated. Whether pregnancy com-
plications also affect CK measures in neonates is yet to be
established.
Creatine supplementation as a therapeutic to alleviate
poor pregnancy outcomes
The ability of creatine to maintain ATP turnover, acid–
base balance, mitochondrial function, together with its
antioxidant, vasodilator, and anti-excitotoxic properties
(Wallimann et al. 2011), make it a candidate for use to
treat ischemic/reperfusion injuries, particular when these
occur in the brain. Whether these properties of creatine
could be exploited to the advantage of the neonate were
first assessed by Wilken et al. (1998) in mouse brain
slices, and by Berger et al. (2004) in brain slices of fetal
guinea pigs, both of which described sustained ATP turn-
over and a reduction in neuronal cell injury when brain
slices were exposed to creatine (Wilken et al. 1998;
Berger et al. 2004). Similar benefits were observed in vivo
with rat pups (Adcock et al. 2002). The ability of creatine
to easily load into neuronal cells prior to birth may mean
that creatine is more effective in neonatal conditions of
acquired brain injury than for adult brain injury [reviewed
by (Dickinson et al. 2014)]. These results lead to sugges-
tions that creatine may act to protect the neonatal brain
from injury induced by intrapartum asphyxia. Studies
conducted by Ireland et al. (2011) identified the neuro-
protective capacity of creatine, administered antenatally
by supplementation of the maternal diet, to protect the
spiny mouse pup from the effects of birth asphyxia (Ire-
land et al. 2011). Specifically, the amelioration of neu-
ronal cell death and maintenance of mitochondrial integ-
rity in the presence of creatine was described. These were
promising results for the treatment of neonatal HIE, but
the overall improvement to survival rate of offspring of
creatine-fed dams lead to thoughts that creatine, when

Creatine for women: a review of the relationship between creatine and the reproductive cycle…
1 3
administered and loaded into fetal organs in utero, might
provide protection to other peripheral organs known to be
highly susceptible to the global oxygen deprivation asso-
ciated with an asphyxic episode at birth (Ireland et al.
2008). Exploration of this hypothesis to date has included
characterisation of the diaphragm muscle and kidney fol-
lowing birth asphyxia. The benefits of creatine loading for
the diaphragm included attenuation of muscle atrophy and
improvement of contractile function, such that function
of this important muscle did not differ from diaphragm
samples obtained from pups from a control birth (Can-
nata et al. 2010). Analysis of the kidney showed birth
asphyxia caused structural damage to the neonatal renal
cortex, medulla and renal papillae in the spiny mouse off-
spring (Ellery et al. 2012), and the presence of changes
in young adult male spiny mice suggest the possibil-
ity that neonatal acute kidney injury has the longer term
risk of developing into chronic kidney injury, in males at
least, where reduced nephron endowment and GFR were
detected (Ellery et al. unpublished observation). As these
studies progress into higher order animal models and
human-based analyses, careful consideration of fetal sex
should be given when reporting outcomes. In our own
animal experiments, only 52 % of male spiny mouse off-
spring survive the birth asphyxia insult, compared to 69 %
of females, suggesting that male fetuses are more vulner-
able to this type of insult (LaRosa et al. 2016). The male
vulnerability to prenatal insults is believed to be a result
of the faster in utero growth rate of males, compared to
females (Eriksson et al. 2010). When we supplement the
diet of the mother with creatine before birth asphyxia, sur-
vival of females is improved by 12 % and male survival is
improved by 19 %, suggesting that creatine is beneficial
to fetuses of both sexes, but perhaps slightly more so for
males. Importantly for the progression of these findings
into the clinic, studies on the safety of supplementary cre-
atine in the pregnant spiny mouse have shown that a high
and prolonged oral dose of creatine does not result in any
adverse outcomes for the mother (Ellery et al. 2015a).
It has also been shown that high exposure to creatine in
utero does not affect the expression levels of the enzymes
required for creatine synthesis, 24 h after birth (Dickinson
et al. 2013). A recent study of maternal dietary creatine
supplementation during pregnancy in rats concluded that
creatine exposure in utero had a positive effect on mor-
phological and electrophysiological development of CA1
neurons. However, this affect persisted beyond the half-
life of creatine and may have the potential to increase
epileptogenic focus (Sartini et al. 2016). Studies are now
underway to determine the safety and efficacy creatine
supplementation during pregnancy, using non-human
primates.
Creatine as a therapeutic for women
As discussed earlier, the effectiveness of creatine as an
ergogenic aid for female athletes is less than that for men.
The possibility that this reflects the cyclic nature of female
sex hormones, and/or the presence or absence of testos-
terone, requires further studies to characterize the differ-
ences of creatine uptake and utilization between men and
women, and how these might change across the menstrual
cycle, with conception and menopause. Despite the paucity
of data around this, there are a number of conditions for
which treatment of women with dietary creatine is proving
highly effective.
Mental illness
Metabolic impairment within the brain initiates the cellular
injury-death cascade, driven by the production of reactive
oxygen species, lipid peroxidation, DNA damage and apop-
tosis. This pathophysiology has been shown to hinder cellu-
lar resilience and contribute to depressive disorders (Fuchs
et al. 2004; Seifried 2007). It has been hypothesized that
damage to mitochondria in the hippocampus and prefron-
tal lobe could compromise the creatine/phosphocreatine
circuit and instigate depression-like behavior (Allen 2012);
indeed, CK activity is inversely related to the severity of a
depressive episode (Dager et al. 2004; Segal et al. 2007).
Healthy females have less phosphocreatine in the frontal
lobe than healthy males (Riehemann et al. 1999). This may
suggest that females are more susceptible to depressive dis-
orders associated with shifts in brain creatine metabolism.
Indeed, depression occurs twice as often in females than
males (Bebbington et al. 2003), with episodes being more
severe, frequent and prolonged (Kornstein et al. 2000).
Dietary creatine supplementation has been considered
as a potential therapy to counter the reductions in brain
metabolism associated with depression. Encouragingly
for women, the associations of estrogens and increased
CK activity have lead to suggestions that creatine sup-
plementation may be more beneficial in treating depres-
sion in females over males (Allen et al. 2010). In studies
conducted in rats, increasing dietary intake to 4 % of daily
food consumption for 5 weeks prior to assessment, signifi-
cantly improved performance on tests such as the forced
swim test, known to identify depressive-like behaviours
(Allen et al. 2010). This result was not present in male rats.
A recent extension of these studies showed that the pres-
ence of sex hormones was essential to the protective effects
afforded by creatine to depressed rats (Allen et al. 2015).
In human studies, the use of dietary creatine as an adjunct
therapy accelerated treatment response in depressed ado-
lescent (Kondo et al. 2011) and adult females (Lyoo et al.

S. J. Ellery et al.
1 3
2003). In a recent pilot study by Hellem et al. (2015), six
females with a major depressive disorder, in addition to
methamphetamine dependence, received dietary creatine
supplementation for a period of 8 weeks. During this time,
the subjects displayed lower levels of depression and anxi-
ety, as evaluated by the Hamilton Depression Rating Scale
and Beck Anxiety Inventory Scales (Hellem and Renshaw
2015).
Another interesting aspect of female mental health and
wellbeing associated with levels of estrogens are episodes
of premenstrual tension (PMT). Low levels of estrogens
can characterize this syndrome, which affects women from
the mid-luteal phase of the menstrual cycle until menstrua-
tion. Whether there is a link between low circulating estro-
gens associated with PMT and creatine metabolism is yet
to be established. However, administration of estrogens at
this time has been shown to reduce cyclic bouts of worsen-
ing mood (Hammarbäck et al. 1985). Such treatment would
be most important for those women who suffer from a rare
form of PMT who undergo severe episodes of depression,
insomnia, forgetfulness and confusion during the mid-
luteal phase of their menstrual cycle (Hammarbäck et al.
1985). Characterization of the hormone profile of these
women show disproportionately low estrogens compared
to progesterone during these depressive episodes (Abraham
1983). As with other depressive conditions, increasing CK
activity through enhanced creatine dietary consumption
may be a safe and beneficial treatment to reduce the symp-
toms of PMT.
Morbidities associated with ageing
Due to the changes in sex hormone production during
and after menopause, females are particularly suscepti-
ble in their older years to bone and muscle degeneration
(Evans 2004). Age-related bone loss is accelerated during
menopause, leading to osteoporosis and contributing to
osteoarthritis (Hernandez et al. 2003). Creatine is show-
ing promise in targeting the progression of these ailments.
The differentiation of bone and cartilage cells is a highly
energy dependent process, which has been previously
shown to utilize the creatine/phosphocreatine/CK circuit
(Wallimann and Hemmer 1994). Whether dietary creatine
supplementation could be used to aid bone regeneration
was first assessed in cultured osteoblast-like cells (Ger-
ber et al. 2005). This study found that the addition of cre-
atine to culture media promoted differentiation of primary
osteoblast-like cells by increasing alkaline phosphatase
activity, and concluded that dietary creatine may be benefi-
cially to aid fracture healing or prevent the progression of
osteoporosis (Gerber et al. 2005). In addition to frail bones,
ageing is associated with sarcopenia or reduced muscle
mass. Together, these conditions reduce the capacity for
rapid muscle contraction, and can lead to loss of balance,
increased falls and injury (Schneider and Guralnik 1990).
Dietary creatine supplementation has thus been trialed in
aged individuals to assess its capacity for rebuilding and/
or maintaining lean muscle and bone mass. When creatine
was given in conjunction with moderate exercise, signifi-
cant improvements in physical function and lower limb
lean mass were observed in aged men and women (Got-
shalk et al. 2008). Preliminary studies in postmenopausal
women aged 50–65 years suffering from osteoarthritis have
also shown that introducing a standard dietary creatine sup-
plementation regime in conjunction with resistance train-
ing improved physical function, lower limb lean mass and
overall, improved quality of life for these women (Neves
et al. 2011).
With an ageing population in the western world, simple
nutritional interventions with the capacity to reduce the
burden of fall related injuries on our healthcare system,
prolong functional independence, and overall improve the
quality of life should be held in the highest regard. Whilst
manipulation of the creatine/phosphocreatine/CK circuit to
target these aliments is somewhat in its infancy, compared
to studies of exercise performance in younger individu-
als, it shows much promise, particularly for women where
changes to hormone production rates underpin tissue loss
and reduced tissue regeneration.
Conclusions and recommendations for future
research
Assessment of the literature as a whole clearly suggests that
males and females store, metabolize and utilize creatine in
a sex-specific manner. However, this remains an incom-
plete story, with evidence spread across an array of studies,
mainly conducted in the 1960s–1990s, where sex-depend-
ent effects were not the primary outcome. As a whole, this
topic of sex-specific differences in creatine metabolisms is
deserving of new investigations using modern technolo-
gies, including in vivo tracer and imaging techniques and
high throughput genomics, to establish which aspects of
the creatine/phosphocreatine/creatine kinase circuit are
most influenced by gender, and which of the isoforms of
creatine kinase are affecting serum CK levels throughout a
female’s reproductive life. There also remains the need to
conduct population-based studies that characterize creatine
homeostasis in women, taking into consideration age, body
composition and stage of the reproductive cycle, and the
further effects of conception, pregnancy, and parturition. It
is probably essential that these studies should be conducted
on cohorts of women followed through the menstrual cycle,
or followed from conception to birth, and then post-par-
tum. Such longitudinal studies would provide data integral

Creatine for women: a review of the relationship between creatine and the reproductive cycle…
1 3
to understanding the adaptability of this phosphagen sys-
tem for females, and how this can be used to optimize and
enhance health outcomes for women.
Acknowledgments HD is an NHMRC Career Development Fel-
low & DWW is a Distinguished Researcher of the Cerebral Palsy
Alliance.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict
of interest.
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