Sports Med 2012; 42 (4): 327-342

REVIEW ARTICLE 0112-1642/12/0004-0327/$49.95/0

ª 2012 Adis Data Information BV. All rights reserved.

Influence of Hormonal Status on Substrate

Utilization at Rest and during Exercise in
the Female Population
Laurie Isacco, Pascale Duché and Nathalie Boisseau
Clermont University, Blaise Pascal University, Laboratory of Metabolic Adaptations to Exercise in
Physiological and Pathological Conditions, Aubière, France

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
2. From Childhood to Adulthood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
2.1 Definition of Sexual Maturity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
2.2 Female Sexual Hormones, Exercise and Substrate Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
2.3 Influence of Physical Training on the Secretion of Female Sexual Hormones . . . . . . . . . . . . . . . . 330
3. Hormonal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
3.1 Menstrual Cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
3.1.1 Definition of the Menstrual Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
3.1.2 Natural Female Sexual Hormones and Substrate Oxidation during Prolonged Exercise . . . 331
3.1.3 Exercise Intensity, Female Sexual Hormones and Substrate Oxidation . . . . . . . . . . . . . . . . 331
3.2 Oral Contraceptives (OCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
3.2.1 Definition of OCs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
3.2.2 OCs, Substrate Oxidation and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
3.2.3 OCs, Substrate Oxidation and Growth Hormone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.3 Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.3.1 Definition of Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.3.2 Menopause and Substrate Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
3.3.3 Menopause, Hormonal Replacement Therapy and Substrate Utilization . . . . . . . . . . . . . . 336
4. Gender Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4.1 Substrate Utilization, Diet and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4.2 Effects of Ovarian Hormones on Substrate Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4.3 Other Hormones Implicated in Gender Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
5. Cellular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
5.1 Cellular Impact of Ovarian Hormones on Substrate Mobilization and Utilization . . . . . . . . . . . . . 338
5.2 The Role of Estrogen Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
6. Conclusion and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Abstract During exercise, substrate utilization plays a major role in performance

and disease prevention. The contribution of fat and carbohydrates to energy
expenditure during exercise is modulated by several factors, including intensity
and duration of exercise, age, training and diet, but also gender. Because sex
hormone levels change throughout a woman’s lifetime (in connection with
328 Isacco et al.

puberty, the menstrual cycle, use of oral contraceptives and menopause), the
female population has to be considered specifically in terms of substrate utili-
zation, and metabolic and hormonal responses to exercise. Before puberty,
there is no difference between males and females when it comes to substrate
oxidation during exercise. This is not the case during adulthood, since women
are known to rely more on fat than men for the same relative intensity of
exercise. Among adult women, the menstrual cycle and use of oral contra-
ceptives may influence substrate oxidation. While some authors have noted
that the luteal phase of the menstrual cycle is connected with greater lipid
oxidation, compared with the follicular stage, other authors have found no
difference. Among oral contraceptive users, fat oxidation is sometimes in-
creased during prolonged exercise with a concomitant rise in lipolytic hor-
mones, as well as growth hormone. If this result is not always observed, the
type of oral contraceptive (monophasic vs triphasic) and hormone doses may
be implicated. Menopause represents a hormonal transition in a woman’s life,
leading to a decline in ovarian hormone production. A decrease in fat oxida-
tion is consequently observed, and some studies have demonstrated a similar
respiratory exchange ratio during prolonged exercise in postmenopausal
women and in men. As is the case during puberty, no sex difference should thus
appear after menopause in the absence of hormonal replacement therapy
(HRT). Results concerning women who take HRT remain conflicting. HRT
may act on fat loss by increasing lipid metabolism, but this depends on how the
treatment is administered (orally vs transdermally). To better understand the
role of ovarian hormones in substrate oxidation, studies have made use of
animal protocols to investigate cellular mechanisms. Estradiol and progester-
one seem to have opposite effects, with greater lipid oxidation when estradiol is
used alone. However, the concentrations used (physiological levels or phar-
macological doses) may considerably modify fuel selection. In cases where
conflicting data are observed in studies of substrate utilization and prolonged
exercise in women, methodological reasons must be called into question. Too
many parameters, which oftentimes are not specified, may modulate substrate
utilization and metabolic and hormonal responses to prolonged exercise. Al-
though information is generally provided about the type of exercise, its dura-
tion and the subjects’ training level, detailed information is not always given
about the subjects’ nutritional state and, more specifically, the hormonal status
of female subjects. The primary purpose of this review was to identify the
impact of hormonal status on substrate oxidation among female subjects at
rest and during exercise. A second aim was to describe gender differences in
substrate utilization during exercise.

1. Introduction Proteins represent 1–8% of energy expenditure

during submaximal exercise.[5] Consequently, this
Carbohydrate (CHO) and lipids are the main review will focus only on CHO and lipid utilization
energy sources mobilized to meet energy needs during exercise, since the contribution of protein to
during muscle contraction. Studies have extensively energy expenditure is considered to be negligible.
investigated the balance between CHO and lipids Exercise intensity is of primary importance
and the factors influencing their respective con- because when the intensity of exercise increases,
tribution to energy expenditure during exercise.[1-4] a shift in substrate utilization toward CHO[1]

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
Substrate Utilization in the Female Population 329

occurs. Age, training, diet, gender and nutritional ‘oral contraceptives’, ‘menstrual cycle’, ‘menopause’,
and hormonal status are likely to influence the ‘ovarian hormones’ and ‘hormonal status’.
balance of substrate utilization, but specific data
concerning women are lacking.[4,6] There is con- 2. From Childhood to Adulthood
siderable evidence that gender affects substrate
utilization during exercise,[7,8] indicating that 2.1 Definition of Sexual Maturity
women rely more on fat metabolism than men for
The primary change occurring at puberty is
the same relative exercise intensity. Differences in
the development of sexual maturation under the
substrate metabolism between males and females
co-ordinated control of the gonadotropic, soma-
are, however, not observed in childhood; they
totropic and adipostat systems.[9] As mentioned in
appear with the onset of puberty, suggesting that sex
section 1, puberty may be described as a critical
hormones impact substrate mobilization, transport
time in which differences appear between males
and utilization.[6] After puberty, women undergo
and females in substrate oxidation rates during
cyclical changes in sex hormone levels through-
exercise due to hormonal changes[6] (see figure 1).
out their lives. During adulthood, the menstrual
Female sexual maturity is determined by an
cycle is characterized by natural fluctuations
increase in ovarian hormone concentrations and
in ovarian hormones. In addition, many women
the development of secondary sexual character-
use oral contraceptives (OCs) that also modify
istics, which takes many years. In 1962, Tanner[10]
hormonal status due to synthetic hormone
proposed a classification system to define matu-
use (ethinyl-estradiol and progestin). Later in
rity progress through the development of breasts
life, hormonal changes occur once again, with
(5 stages), genital organs (5 stages) and pubic hair
a decrease in ovarian hormone production at
(6 stages). Puberty appears between stages 4 and
menopause.
5, which allows distinguishing between pre-
The primary purpose of this review was to
adolescents and adolescents. The Tanner scale is
identify the impact of hormonal status on sub-
still in use today despite limitations due to diffi-
strate oxidation at rest and during exercise in fe-
culties differentiating between different phases,
male subjects. A second aim was to describe the
such as breast stages B4 and B5.
gender difference in substrate utilization during
exercise.
2.2 Female Sexual Hormones, Exercise and
Since data in the literature about energy me- Substrate Utilization
tabolism among female subjects are limited, all
references found in book chapters (n = 5) as well The most potent estrogen in women’s bodies,
as original articles from PubMed (n = 98) that 17b-estradiol, is produced by the ovaries. Estra-
were relevant to our topic have been included. diol blood concentrations are related to the stage
Keywords used in the method research were ‘pu- of sexual maturity[11] and increase gradually from
berty’, ‘females or women’, ‘males’, ‘animals’, ‘ex- breast stages B1 to B3 (mean values 1.8–2.2 ng/dL).
ercise’, ‘energy metabolism’ and ‘substrate oxidation They then rise dramatically from the onset of
or utilization’. More specific words also used were sexual maturation (B3; mean value 2.2 ng/dL) to

Puberty Menstrual cycle OC Menopause

Maturation stages Menstrual phase OC type Hormonal treatment

→ Breast stages → Follicular → Monophasic Type and doses
(Tanner stages) → Ovulation → Biphasic
→ Luteal → Triphasic
Doses
→ Progestin
→ Estrogen

Fig. 1. Hormonal changes during the life of a woman. OC = oral contraception.

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
330 Isacco et al.

B4 (mean value 4.2 ng/dL) and even more so from substrate metabolism between girls at different
B4 to adulthood (B5; with a mean value of stages of sexual development.[13]
11 ng/dL).[11] Viru et al. [12] designed a 3-year lon- At puberty, girls have greater adipose tissue
gitudinal study in which they monitored the hor- development due to estrogen; whereas muscle
monal response to exercise in a cohort of 34 girls mass development is higher in boys due to tes-
initially aged 11–12 years. Basal concentrations of tosterone.[18] Changes in the total amount of
17b-estradiol and progesterone were significantly body fat may also contribute to substrate oxida-
higher for breast stage B4. In response to 20 min- tion differences between male and female subjects
utes of .exercise at 60% of maximal oxygen consump- at rest and during exercise.[19]
tion (VO2max), 17b-estradiol, progesterone and Increases in ovarian hormone concentrations
testosterone concentrations were higher at stage occurring at menarche modify substrate utiliza-
B5 than at other stages (percentage increase from tion, but other factors, such as intensive physical
baseline pre-exercise values), showing increased training, could also influence ovarian produc-
hormonal responsiveness to intense exercise in tion and thus may affect energy metabolism
line with sexual maturation in girls. during exercise.
Timmons et al.[13] investigated the effect of
puberty on substrate oxidation
. during 60 minutes
2.3 Influence of Physical Training on the
of exercise at 70% of VO2max. They compared Secretion of Female Sexual Hormones
14-year-old adolescent girls who had regular
menstrual cycles to 12-year-old pre-adolescent During childhood and adolescence, intensive
girls. The girls’ maturity was self-assessed and physical training could disturb metabolic and
based on the Tanner breast stages.[10] The au- hormonal regulation, which may lead to primary
thors stated that this method had been validated and secondary amenorrhoea and a decrease in
and is reproducible in girls.[14] To provide more reproductive capacity.[20,21] Endorphin secretion
objective and reliable information, serum estra- is increased with high levels of physical activity,
diol levels were also determined for each girl. The particularly when associated with caloric restric-
subjects performed exercise with and without tion, leading to hypothalamic activity dysregu-
exogenous CHO intake. The authors showed lation, a decrease in the pulsatile frequency of
that the lipid oxidation rate during exercise gonadotropin secretion that results in the suppres-
(calculated using Peronnet and Massicotte’s sion of estrogen, and, ultimately, late pubertal matu-
equations[15]) was higher and the serum estradiol ration and oligo- or amenorrhoea.[22]
concentrations, total CHO and endogenous Regulation of the hypothalamic pituitary axis
CHO oxidation rates lower in 12-year-old girls depends on the type of sports being practiced;
when compared with the 14-year-old girls during sports that require high-level training combined
the session without exogenous CHO intake. With with dietary restrictions place women at an in-
exogenous CHO intake, endogenous CHO oxi- creased risk of developing the ‘female athlete
dation rates were more elevated in 14-year-old triad’, a syndrome that consists of eating dis-
girls, compared with 12-year-old girls but no sig- orders, amenorrhoea and osteoporosis.[20] Elite
nificant difference appeared for lipid, total and gymnasts, for example, tend to reach menarche at
exogenous CHO oxidation rates.[13] This suggests a later age along with menstrual dysregulation
that diet may influence fat utilization in an (amenorrhoea, oligomenorrhoea, anovulation,
age-dependant manner. Acute estrogen supple- luteal phase deficiency) due to hormonal altera-
mentation in rats increases fat oxidation during tions caused by low calorie intake combined with
exercise.[16,17] However, plasma estradiol levels high physical activity levels.[23]
are unrelated to substrate oxidation during Therefore, the type of sport athletes pursue,
exercise in girls. Other hormones, such as glu- and their level of physical training, could have an
corticoids, growth hormone (GH) and enzyme impact on the onset of puberty and menstrual
activities, are likely to explain the differences in cycle regulation. Ovarian hormone secretion may

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
Substrate Utilization in the Female Population 331

be affected, and could play a role in substrate change appears in whole-body respiratory exchange
utilization during exercise. ratio (RER),[34] basal plasma glucose[35] and free-
After puberty, women undergo changes in fatty acids (FFAs)[36] under resting conditions.
sexual hormones due to menstrual cycle regula- Other studies in women (aged 18–40 years)
tion, the use of OC and menopause, which may have shown greater lipid and lower CHO oxida-
affect energy use and storage at rest and during tion rates during exercise trials performed during
exercise. the LP, compared with the FP.[37-41] High estra-
diol concentrations during the LP have been
3. Hormonal Status associated with a decreased glucose rate of ap-
pearance (Ra) and disappearance (Rd) during
3.1 Menstrual Cycle exercise. Estradiol administration to amenor-
3.1.1 Definition of the Menstrual Cycle rhoeic women for 3 days and 6 days decreased
The menstrual cycle is characterized by two plasma glucose Ra and Rd when . subjects ex-
distinct phases of approximately 14 days: the ercised for 90 minutes at 65% of VO2max.[42] The
follicular phase (FP) and the luteal phase (LP). same effect has been observed in regularly men-
The follicular phase starts on the first day of struating women (aged 23.6 – 1.1 years)[39] who
menstruation and lasts about 10–14 days, until performed two 25-minute cycling tests at 70% of
ovulation. The follicular phase is followed by LP, their lactate threshold (LT) intensity and at 90%
which ends on the first day of the next menstrual of LT. The decreased glucose Ra and Rd were
period[24] (see figure 1). Estrogen and progesterone accompanied by lower CHO oxidation and lac-
concentrations vary between the two phases. tate concentrations, indicating less CHO use
During FP, there is a gradual increase in follicle- overall during the LP, compared with the FP. In
stimulating hormone (FSH) and in concentrations addition, levels of non-sexual hormones also vary
of estrogen, which are higher than progesterone. over the course of the menstrual cycle and
Around the fourteenth day of the menstrual cycle, are likely to affect substrate utilization during
there is a luteinizing hormone (LH) peak and the exercise. Increases in cortisol,[43] GH levels[35]
rapid production of estrogen leading to ovulation. and sympathetic activity[44] associated with a de-
Then during the luteal stage both estrogen and cline in insulin action[45] during LP could facil-
progesterone levels are elevated.[25-27] Ovarian itate greater lipid oxidation.
hormone changes throughout the menstrual cycle
3.1.3 Exercise Intensity, Female Sexual Hormones
may alter substrate utilization at rest and during
and Substrate Oxidation
exercise.[28,29]
Exercise intensity appears to be an important
3.1.2 Natural Female Sexual Hormones and factor affecting substrate oxidation during ex-
Substrate Oxidation during Prolonged Exercise ercise and, additionally, the action of female
Several studies have investigated the effect of steroid hormones on fuel metabolism. Hackney
estrogen and, to a lesser extent, progesterone on et al.[46] observed differences in substrate oxida-
substrate metabolism during exercise.[29-32] Men tion rates during exercise of
. low to moderate in-
(aged 21 – 1 years) and women (aged 22 – 2 years) tensity (35% and 60% of VO2max . ) but not in the
to whom estrogen is administered show improved high intensity domain (75% of VO2max). By con-
endurance performance, while muscle and liver trast, other authors have described higher lipid
glycogen are spared and fat oxidation is in- and lower CHO utilization
. with exercise intensity
creased.[29] Consistent with these findings, levels above 50% of VO2max.[37,39] Furthermore,
Hackney[28] has reported that high estrogen levels in these studies, high circulating concentrations
during the LP are associated with the sparing of of sex steroid hormones resulted in an enhanced
muscle glycogen in comparison to the FP, during reliance upon the oxidation of lipid as an energy
which estrogen concentrations are lower.[33] substrate and, consequently, induced a reduction
Throughout the menstrual cycle phases, no in CHO oxidation.

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
332 Isacco et al.

Some authors have observed no differences in hormones vary three times per cycle to mimic the
substrate utilization during exercise at different natural menstrual cycle. Biphasic OC is prescribed
phases of the menstrual cycle. Horton et al.,[35] less often and does not appear to present any real
studied 13 eumenorrhoeic, lean healthy women advantage compared with the other types of OC
(18–39 years of age) who . performed a 90-minute pill.[51,52] Biphasic OC does not offer any practical
cycling test at 50% of VO2max. They observed no benefits and does not reflect a woman’s menstrual
differences in whole-body CHO and lipid oxida- cycle (see figure 1). The progesterone-only pill can
tion rates in the mid-LP, early-FP and mid-FP be prescribed in certain situations (e.g. sensitivity to
phases. Similarly, other studies reported no dif- the estrogen component).
ferences in substrate oxidation rates in resting Estrogen doses have evolved significantly over
and exercise conditions.[47-49] In a recent study by time since the introduction of the OC pill. In the
McLay et al.,[50] nine moderately trained women 1960s, estrogen concentrations were close to
performed an intermittent cycling test followed 150 mg EE and the progestin component could
by a 16 km time trial at the mid-FP and mid-LP reach 250 mg. Very quickly, EE concentrations
phases after 3 days of a normal diet (5.2 g/kg/day) were decreased to 50 mg to offset the negative
and 3 days of CHO loading (8.4 g/kg/day). Time- effects of the OC (insulin resistance and dyslipi-
trial performance was not affected by diet or by daemia). Among the various types of OC cur-
the menstrual-cycle phase, despite lower resting rently available, low-dose EE (less than 35 mg) is
glycogen concentrations in the mid-FP after the most popular (20 mg and 30 mg). Progestin
a normal diet compared with the three other doses are more variable and third generation
situations. In addition, there was no difference in forms of progestin, such as gestodene, have
substrate oxidation during exercise at different also been developed. These new forms minimize
phases of the menstrual cycle. certain side effects, such as insulin resistance,
Discrepancies remain with respect to the effect decreased glucose tolerance, high plasma choles-
of menstrual cycle hormone changes on substrate terol and triglycerides levels.[51] In 2008, a study[54]
oxidation during exercise. Some authors empha- enrolling both users and non-users of the OC
size greater lipid reliance during the LP, although (OC+ and OC-), compared the metabolic profiles
others report that they observed no differences of women aged 34.7 – 7.6 years. It showed that
between the two phases. The type of exercise OC+ women had a higher risk of cardiovascular
(duration, intensity) and the subject’s nutritional disease compared with OC- women. However,
status could explain these results. detailed information about the exact composition
of the OC pills used in the study was not pro-
3.2 Oral Contraceptives (OCs) vided, which limits data interpretation.

3.2.1 Definition of OCs 3.2.2 OCs, Substrate Oxidation and Exercise

OCs may be used by women to not only pre- Some studies have shown that OC does not
vent unwanted pregnancy, but to also control the affect fat oxidation rate and lipolysis at rest when
menstrual cycle and premenstrual symptoms, OC- women (aged 28 – 1 year) are compared with
as well as to improve bone health.[51,52] Women OC+ women (aged 30 – 2 years).[55] Synthetic
with bone diseases may present as estrogen defi- hormone use is known to interfere with substrate
cit, which OC intake may at times counteract.[53] utilization during exercise in rats and in
Three types of OC can be prescribed, usually humans.[56,57] Casazza et al.[58] have investigated
combining ethinyl estradiol (EE) and progestin. the effect of triphasic OC on lipid utilization
Different combination pills include monophasic, during exercise in eight eumenorrhoeic women
biphasic and triphasic forms. Monophasic OC (aged 24.5 – 1.3 years) who performed . two
provides constant hormonal concentrations dur- 60-minute rounds
. of exercise at 45% of VO 2max
ing the menstrual cycle and offers the advan- and 65% of VO2max. The tests were performed
tage of being easy to use. With triphasic OC, again after 4 months of OC utilization, during the

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
Substrate Utilization in the Female Population 333

third week of OC use and during the inactive CHO sparing in OC+ women. A similar study
phase (no synthetic ovarian steroids). The women involving eight OC+ women and 8 OC- (aged
in the study showed greater triglyceride mobili- 21–30 years) reported a decrease in total CHO
zation during exercise
. when using OC (60 min- utilization at the fortieth and fiftieth minutes
utes
. at 45% of VO 2max and 60 minutes at 65% of of exercise in OC+ women compared with
VO2max) but showed no change in FFA oxida- OC– women . (90 minutes of treadmill exercise at
tion. It is likely that an increase in FFA re- 50% of VO2max). These results were associated
esterification may explain these results.[59] with greater plasma GH levels and lower plasma
Although they increase lipolytic activity, glucose values in OC+ women compared with
synthetic ovarian hormones do not exert any OC- women.[57] However, there was no differ-
effect on whole-body or plasma FFA oxidation ence in fat oxidation between the two groups,
during moderately-intense exercise performed which indicates that GH has only a minor effect
in the postprandial state. It is important to note on fat metabolism. Moreover, the authors sug-
that these studies were carried out 3 hours gested that the contradictory findings of no in-
after subjects had consumed food; the results crease in fat utilization despite greater CHO
may be different when subjects have been fasting. sparing in OC+ could be due to gonadal steroid
Suh et al.[40] emphasized that OC use decreases effects on muscle and hepatic tissues, and that
glucose flux with no effect on CHO and lipid this discrepancy could also be explained by pro-
oxidation. tein utilization, which was not assessed.
OCs have been also hypothesized to affect fuel Another study showed no reduction in glucose
selection during prolonged exercise with CHO tolerance among women taking an OC (aged
supplementation.[60] When substrate oxidation was 22.6 – 1.3 years) compared with controls (aged
measured
. during exercise (120 minutes at 57% of 21.3 – 1.3 years) who were given glucose (0.5 g/kg)
VO2max) using indirect calorimetry combined with at
. the onset of 30 minutes of exercise at 60% of
the use of 13C glucose, no differences were ob- VO2max, even though plasma GH concentrations
served in exogenous and endogenous CHO oxida- were higher in women taking OC.[61] Finally,
tion rates between OC+ and OC- subjects and who continuous and intermittent exercise induced a
ingested glucose (2 g/kg) after following a high- greater total GH response in women using an
CHO diet (80% CHO). OC.[62] Overall, these results suggest that the
synthetic hormones contained in an OC have an
3.2.3 OCs, Substrate Oxidation and impact on GH production that may affect sub-
Growth Hormone strate metabolism (table I).
It has been suggested that a shift takes place With low-dose monophasic pills being pre-
from CHO to lipid utilization in skeletal muscle scribed increasingly often, studies are needed to
during exercise in women who use OCs. A sig- better understand their effects on GH secretion
nificant increase in plasma FFA and a decline in and metabolism.
plasma glucose concentrations
. during 30 minutes
of exercise at 40% of VO2max has been observed in
OC+ subjects compared with controls.[32] How- 3.3 Menopause
ever, no differences in RER values were observed
either at rest or during exercise between the two 3.3.1 Definition of Menopause
groups. Plasma GH levels were higher in the OC+ The transition into menopause corresponds
group. The authors of this study suggested that in with a decline in sex steroid hormones, and plasma
spite of its lipolytic action, GH secretion has a estrogen reaches levels similar to those observed in
limited impact on energy metabolism because of men (i.e. 6–24 ng/dL).[63] In addition, adiposity
reduced GH efficiency, lower receptor sensitivity frequently increases with menopause.[64,65] Sub-
and/or a transport bias. GH also has impacts that strate utilization during exercise could thus be ex-
offset the effects of insulin, which could explain pected to change at this time.

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
 Table I. Influence of oral contraceptives on energetic metabolism at rest and during exercise in the female population

334
Study (y) Population OC pills Rest/exercise RER Other parameters
n Status Age (y)a Hormonal status Monophasic Triphasic
Jensen 26 Healthy OC-: 28 – 1 Cross-sectional study 30–35 mg EE Rest = Fat oxidation =
et al.[55] OC+: 30 – 2 13 OC- (no progestin Lipolysis =
(1998) information about components: OC+: plasma
menstrual cycle) desogestril, triglycerides ›
13 OC+ (during levonogestril, compared with OC-
medication) ethinodiol
Bonen 15 Healthy 19–24 Cross-sectional 50 mg mestranol and Walk: 30 min at 40% = OC+: › of absolute
.
et al.[32] study 1 mg norethindrone of VO2max + 30 min at free-fatty acid (exercise
(1991) 8 OC-: FP and LP 50 mg EE and 0.5 mg . .
85% of VO2max at 40% of VO2max)
7 OC+: OC use and norgestrel compared with OC-
OC non-use 30 mg EE and 0.3 mg GH: OC+ > OC- during
norgestrel moderate exercise

ª 2012 Adis Data Information BV. All rights reserved.

Bemben 16 Moderately 21–30 Cross-sectional study 35 mg EE and 0.5; Treadmill: 90 min at OC+ < OC- at OC+: fl CHO utilization
.
et al.[57] active 8 OC-: LP 0.75 or 1 mg 50% of VO2max 40 and 50 min compared with OC-
(1992) women 8 OC+: pill use norethindrone 35 mg of exercise GH: OC+ > OC- at 10
EE and 1 mg and 20 min of exercise
ethynodiol diacetate
Suh 8 Moderately 22–30 Longitudinal study Day 1–7: 0.035 mg Leg-ergometer = OC+: fl glucose flux at
et al.[40] healthy OC-: FP and LP EE and 0.18 mg cycling: 60 min at exercise compared
.
2003 active OC+ (4 mo): inactive norgestimate 45% of VO2max with OC-
and active phases Day 8–14: 0.035 mg 60 min at 65% of
EE and 0.215 mg .
VO2max
norgestimate
Day 15–21: 0.035 mg
EE and 0.25 mg
norgestimate
Day 22–28: absence
of synthetic hormones
Casazza 8 Moderately 24.5 – 1.3 Longitudinal study Day 1–7: 0.035 mg Leg-ergometer = OC use: › triglyceride
et al.[58] healthy OC-: FP and LP EE and 0.18 mg cycling: 60 min at mobilization
.
(2004) active OC+ (4 mo): inactive norgestimate 45% of VO2max
and active phases Day 8–14: 0.035 mg 60 min at 65% of
EE and 0.215 mg .
VO2max
norgestimate
Day 15–21: 0.035 mg
EE and 0.25 mg
norgestimate
Day 22 to 28:
absence of synthetic
hormones

Continued next page

Sports Med 2012; 42 (4)

Isacco et al.
 Table I. Contd
Study (y) Population OC pills Rest/exercise RER Other parameters
n Status Age (y)a Hormonal status Monophasic Triphasic
Jacobs 8 Moderately 24.5 – 1.3 Longitudinal study Day 1–7: 0.035 mg Leg-ergometer = OC use: › lipolytic
et al.[59] healthy OC-: FP and LP EE and 0.18 mg cycling: 60 min at rate and › fatty-acid
.
(2005) active OC+ (4 mo): norgestimate 45% of VO2max re-esterification
inactive and Day 8–14: 0.035 mg 60 min at 65% of
active phases EE and 0.215 mg .
VO2max
norgestimate
Day 15–21: 0.035 mg
EE and 0.25 mg
norgestimate
Day 22–28: absence
of synthetic
hormones

ª 2012 Adis Data Information BV. All rights reserved.

Substrate Utilization in the Female Population

Tremblay 12 Moderately OC-: Cross-sectional Unknown Cycling exercise = No difference in fuel

et al.[59] healthy 24.7 – 0.8 study 4 ·120 min at 50% selection between OC+
(2010) active OC+: OC-: FP of MPO: and OC-
24.6 – 1.2 OC+: pill use Glucose + mixed diet
Water + mixed diet
Glucose + high
CHO diet
Water + high CHO
diet

Bernardes 7 Healthy 22–31 Longitudinal study 6 days: 30 mg EE 6 days: 30 mg EE and Leg-ergometer Unknown GH: OC+ > OC- at 10
et al.[62] OC+: tested during and 50 mg 50 mg levonorgestrel cycling: continuous: and 20 min in both
1998 the phases of OC levonorgestrel 5 days: 40 mg EE and 20 min at 60% of types of exercise
.
use and OC non-use 5 days: 40 mg EE 75 mg levonorgestrel VO2max Total GH response
and 75 mg 10 days: 30 mg EE Intermittent: 12.5 min (AUC):
levonorgestrel and 125 mg . OC+ > OC-
at 80% of VO2max and
10 days: 30 mg EE levonorgestrel 7.5 min of rest
and 125 mg 7 days: 35 mg EE and
levonorgestrel 0.5 mg norethindrone
7 days: 35 mg EE 7 days: 35 mg EE and
and 0.5 mg 0.75 mg
norethindrone norethindrone
7 days: 35 mg EE 7 days: 35 mg EE and
and 0.75 mg 1 mg norethindrone
norethindrone

Continued next page

Sports Med 2012; 42 (4)

335
 336 Isacco et al.

AUC = area under the curve; CHO = carbohydrate; EE = ethinyl estradiol; FP = follicular phase; GH = growth hormone; .LP = luteal phase; MPO = maximal power output; OC = oral
contraceptives; OC+ = OC users; OC- = OC non-users (eumenorrheic women); RER = respiratory exchange ratio; VO2max = maximal oxygen consumption; < indicates lower;
3.3.2 Menopause and Substrate Utilization
Respiratory. exchange ratio and fat oxidation
Other parameters

exercise: glucose
ingestion before
adjusted for VO2 (mmol/min) during submaximal

tolerance OC-
OC+ = glucose

GH response:
Oral glucose

OC+ > OC-

work
. (exercise on a cycle ergometer at 45% of
tolerance VO2max for 30 minutes) are the same in 70-year-old
men and 66-year-old women.[66] The higher reliance
on fat as substrate in women thus decreases at
menopause and may be attributed to a decline in
plasma estrogen (and progesterone) concentrations.
30 min cycling at 60% Unknown

> indicates higher; = indicates a nonsignificant difference between groups; › indicates a significant increase; fl indicates a significant decrease.
However, RER is lower with .obesity and, after
RER

40 minutes of cycling at 50% of VO2max,[67] fat oxi-

dation, adjusted for fat-free mass, is higher in post-
menopausal women compared with men (aged
57.2 – 1.2 years). These results were observed despite
Rest/exercise

similar basal plasma 17b-estradiol concentrations in

of VO2max

the two groups and higher plasma FFA levels in

men. The increase in plasma estrogen concentra-
.

tions observed in premenopausal women[68] induced

by exercise, may still occur in postmenopausal obese
women and explain higher fat oxidation rates when
compared with men.[67]
Triphasic

3.3.3 Menopause, Hormonal Replacement Therapy

and Substrate Utilization
Among lean postmenopausal women compared
<1 mg progesterone
35 mg EE and 1 mg
7 days: 35 mg EE

with lean premenopausal women, a decrease in

<50 mg EE and
norethindrone

norethindrone

plasma ovarian hormones and a diminished

Monophasic

capacity for fat oxidation could explain increased

and 1 mg
OC pills

adiposity at menopause. Hormonal replacement

therapy (HRT) [i.e. 0.625–1.25 mg/day of estro-
Age data are presented in means – standard deviations or ranges.

gen] is sometimes prescribed to limit cardio-

vascular risk and metabolic diseases that may
Hormonal status

Cross-sectional

7 OC+: pill use

occur at menopause[69] (see figure 1). The two

7 OC-: LP

methods of administering estrogen, orally or

transdermally, have different effects on energy
study

metabolism and fuel selection.[70-72] Some studies

have shown that HRT enhances exercise-induced
Age (y)a

fat loss in older women due to its action on lipo-

20–25

lytic hormone activities and secretions.[73,74]

During exercise, postmenopausal women taking
HRT also respond with higher plasma levels of
physically
14 Healthy

lipolytic hormones, such as cortisol or GH,

Status
Population

active

compared with women not taking HRT.[75,76]

However, in response to acute exercise, Johnson
n
Table I. Contd

et al.[77] observed no differences in fat utiliza-

tion rates between women taking HRT (aged
Boisseau
Study (y)

et al.[61]

53.0 – 2.98 years) and the control group (aged

(2001)

49.38 – 3.07 years) after exercising for 30 minutes

a

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
Substrate Utilization in the Female Population 337

.
on a treadmill at 80% of VO2max. One cannot rule 4. Gender Differences
out the possibility that exercise intensity may
4.1 Substrate Utilization, Diet and Exercise
mask differences in fat oxidation between women
taking HRT and those not taking HRT. Many studies have investigated gender differ-
In a crossover design study involving healthy ences in substrate oxidation rates during exercise
postmenopausal women (aged 57 – 1 years), in young subjects. Overall, these studies reveal
O’Sullivan et al.[71] have shown that, at rest, oral that, for the same relative exercise intensity,
HRT for 24 weeks was associated with decreased women show greater reliance on lipids . than
lipid oxidation, increased fat mass and decreased men[7,8,82] at moderate intensity (65% of VO 2max)
.
lean body mass, when compared with 24 weeks among men and women matched for VO 2max,
[83]
.
of transdermal HRT. In addition, 24 hours of and at high intensity (80% of VO2max). [84]

indirect calorimetry measurements have clearly Tremblay et al.[60] studied the effects of pre-
shown a decrease in lipid oxidation at rest in exercise diet on substrate metabolism during ex-
postmenopausal women (aged 51.3 – 3.9 years) ercise in men and women. They observed that
receiving oral estrogen treatment (0.625 mg/day) during exercise preceded by 2 days of mixed
for 2 months.[70] Reduced fat utilization could be diet, the contribution of CHO to total energy
explained by a decrease in the activities of en- expenditure was higher in men than in women
zymes of lipolysis, such as hormone sensitive whether or not women used OC. However, when
lipase; or lipid oxidation, such as carnitine palmi- women and men were fed with a high-CHO diet
toyltransferase, following exposure of the liver for 2 days before performing exercise, and in-
to high estrogen concentrations.[78] The liver ac- gested glucose before and during exercise, the
counts for approximately 25% of whole-body CHO oxidation rate during exercise increased for
resting metabolism[79] and oxidizes more fat than both groups; there was no longer any difference
does skeletal muscle. Moreover, estrogen passes between men and women. This study highlights
through the liver with oral but not transdermal the importance of nutritional status in studies
administration, increasing GH and GH-binding comparing men and women.
protein levels and decreasing insulin-like growth
factor (IGF)-1 with an impact on substrate 4.2 Effects of Ovarian Hormones on
metabolism and body composition.[71,80] Indeed, Substrate Utilization
lipid oxidation is increased in postmenopausal
women (45–65 years of age) taking transdermal Studies in men who received estrogen treat-
treatment, while it is decreased among women ment have confirmed the link between estrogen
who take oral estrogen treatment.[72] It is im- and substrate oxidation[85] by showing increased
fat oxidation rates and decreased CHO oxidation
portant to point out, however, that all studies
rates during exercise. Animal studies have pro-
investigating the impact of the route of adminis-
vided data supporting these results[33] by showing
tration have been conducted at rest; exercise
studies are still lacking. that male rats who receive estrogen have in-
HRT may have repercussions on the cardio- creased FFA and triacylglycerol muscle content,
vascular system and the development of breast and thus more lipids available as substrate, and
cancer, which led to a decline in its usage.[81] they spare more glycogen during exercise when
compared with control rats.
However, these data must be interpreted with
care, since most of the studies used Premarin
4.3 Other Hormones Implicated in
(conjugated estrogens) rather than lower E2 Gender Differences
concentrations from transdermal administration
(17b-estradiol). It thus appears necessary to con- Differences in substrate metabolism may be
tinue research on types of HRT and dosage in affected by factors other than the direct action of
order to better understand the potential risks and estrogen and progesterone on muscle and adipose
benefits for the health of postmenopausal women. tissue. It has been suggested that an increase in

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
338 Isacco et al.

b-adrenergic sensitivity and a decrease in a- A study of female mice given oral treatment
adrenergic sensitivity can explain higher lipolytic with natural (17b-estradiol and progesterone)
activity in women.[86] GH, insulin and cortisol and synthetic (EE and norethisterone acetate)
action also play a significant role in lipid mobili- hormones (either alone or in combination) for
zation and storage. Bunt[87] has reported lower 24 days revealed that each treatment enhanced
RER during exercise in women than in men, and hepatic glycogen deposition. It also showed a
suggested an increase in GH response to exercise greater increase with 17b-estradiol alone and
in women, which leads to greater fat oxidation revealed that progesterone antagonized the es-
due to GH lipolytic action. Other studies, how- tradiol glycogenic effects.[96]
ever, have reported differences in substrate utili- Hatta et al.[97] designed a study looking at the
zation during exercise between men and women effect of an 8-day hormonal treatment on exercise
with a higher GH response in men, and they do metabolism in ovariectomized rats. Rats were
not support the conclusions of Wideman et al.[88] given either estradiol alone, estradiol and pro-
Additional studies are therefore needed to im- gesterone or sesame oil (control), and then ran
prove our understanding of the role of the so- for 60 minutes at 25 m/min. Results showed
matotrope axis. that FFA oxidation was increased and CHO
In summary, gender differences in substrate stores were spared with estrogen alone, as com-
utilization in the premenopausal state during ex- pared with the treatment combining estrogen and
ercise have been well documented. Women rely progesterone.
more heavily on fat than do men for the same Studies looking at the influence of different
intensity of exercise, mainly because of the action estradiol doses on metabolic responses to max-
of estrogens.[29,68,82,89-92] imal and submaximal exercise in rats have also
shown a positive relationship between estrogen
dose and exercise time to exhaustion. With in-
5. Cellular Mechanisms
creased estrogen doses there was greater muscu-
We have previously established that substrate lar and hepatic glycogen sparing and better lipid
utilization during exercise is affected by age, utilization.[17,98] Campbell and Febbraio[37] have
hormonal status and gender.[7,12,58] Studies have shown that ovariectomized rats have a decrease
investigated the cellular mechanisms of estrogen in contraction-stimulated glucose uptake com-
and progesterone action in order to better un- pared with control rats, which is reversed with
derstand their effects on substrate metabolism. 17b-estradiol replacement. Again, at physiologi-
cal levels, progesterone inhibited the effect of es-
tradiol. Few studies have explored this topic, but
5.1 Cellular Impact of Ovarian Hormones on
Substrate Mobilization and Utilization
there is some evidence suggesting that ovarian
hormones act on glucose transporter-4 translo-
Wilson et al.[93] demonstrated that at rest cation rather than on total protein content.[56]
exogenous estrogen administration leads to a Ovarian hormones also play a key role in the
shift in the triglyceride fatty-acid flux from stor- activity of lipid oxidation enzymes. Ovariecto-
age in the adipose tissue to incorporation by mization in rats is associated with a decrease in
muscle. This study demonstrated that estrogen carnitine palmitoyltransferase I (CPT I) and b3-
affects both the synthesis and the storage of fatty hydroxyacyl-CoA dehydrogenase (b-HAD) ac-
acids. In male rats administered with estradiol, tivities, restored by estrogen treatment but not
muscle lipoprotein lipase (LPL) activity and progesterone treatment.[56] When the two hor-
ratio of muscle to adipose LPL activity have mones were combined, the effect on enzymatic
been shown to increase the directing of plasma activities was the same as ovariectomization,
triacylglycerol-derived fatty acids toward muscle showing the ability of progesterone to inhibit
tissue, where they are stored.[16] Other studies in estrogenic effect. Ovarian hormones also affect
rats have led to similar conclusions.[94,95] b-HAD activity, which is involved in the oxida-

ª 2012 Adis Data Information BV. All rights reserved. Sports Med 2012; 42 (4)
Substrate Utilization in the Female Population 339

tion of short-chain fatty acids, whereas CPT I is and CHO metabolism, specifically the action of
involved in long-chain fatty acid utilization.[97] In estradiol and progesterone at physiological levels
this publication, the authors suggested that and pharmacological doses.
ovarian hormones may upregulate enzyme gene
transcription and subsequently modify their 6. Conclusion and Perspectives
protein levels. Hatta et al.[97] also showed that at
physiological levels, but not with pharmacolog- In this review paper, studies that were presented
ical doses, the lipolytic effects of estrogen are demonstrated that age, menstrual cycle, OC use,
inhibited by progesterone. This could be of par- menopause and gender, may influence relative lipid
ticular value for the treatment of amenorrhoeic and CHO metabolism under resting conditions
or postmenopausal women if the transposition of and during prolonged physical activity. Further-
animal studies can be made to humans. Finally, more, natural ovarian hormones, especially estra-
ovarian hormones may upregulate enzyme gene diol, appear to play an important role in such
transcription and modify their protein levels.[97] adaptations. Indeed, from animal studies, it has
D’Eon et al.[99] showed that ovariectomized been established that estrogen (and more specifi-
rats had increased adiposity, which was reversed cally 17b-estradiol), as well as progesterone, has a
by estrogen treatment. Estrogen induced a de- potential impact on substrate oxidation: estrogen
crease in hyperplasia, hypertrophy and expres- promotes lipid oxidation and glycogen sparing,
sion of lipogenic genes in adipocytes, skeletal whereas progesterone counteracts these actions.
muscle and liver. Estrogen also promoted the Discrepancies occur when studying fuel selection
utilization of lipid as substrate with increased li- in women at rest or during exercise, a partial ex-
polytic activity, stimulation of pathways involved planation may be linked to methodology. Thus, in
in fat metabolism in skeletal muscle and decreased eumenorrhoeic female subjects, the exact stage of
lipogenesis in adipocytes, liver and muscle. the menstrual cycle has to be precisely determined
(early or late FP, ovulation, early or late LP). In the
same way, in women taking OC or HRT, informa-
5.2 The Role of Estrogen Receptors
tion about the types and doses must be given in
Estrogen acts through estrogen receptors detail, since these factors may affect metabolic and
(ERs), namely ERa and ERb. Alonso et al.[100] hormonal adaptations at rest and during exercise.
studied ER knockout mice that had been geneti- At this point, it seems important to pursue in-
cally modified to remove ER. The mice showed vestigations on hormonal status and physiological
an increase in adipocyte size and number, sug- exercise-induced responses in women, in order to
gesting that ERs play a key role in adipose reg- clarify specific hormonal and metabolic responses
ulation, as ER suppression increases fat storage leading to specific fuel selection. Moreover, cellular
and lipolysis inhibition. Similar results in mice studies appear to remain necessary to consider the
were observed by other authors.[101,102] D’Eon complex inherent mechanisms of such adaptations.
et al.[103] specifically demonstrated that estrogen
acts through ER to increase 50 -AMP-activated Acknowledgements
protein kinase (AMPK) expression. Ovarian
hormones could act on substrate utilization No funding was provided for the design and conduct of the
literature search or the collection, management analysis and
through pathways depending on peroxisomal interpretation of the literature.
proliferator-activated receptors (PPARs), since The authors have no conflicts of interest that are directly
PPARg expression is upregulated by 17b-estra- relevant to the content of this manuscript and no one else has
contributed to this research.
diol administration and PPARa expression is
upregulated by 17b-estradiol and progesterone.
In summary, further studies are needed to in- References
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Blaise Pascal, UFRSTAPS Clermont Ferrand, Laboratoire
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