The mystery of female connective tissue

Michael Kjær and Mette Hansen

J Appl Physiol 105:1026-1027, 2008. First published 7 August 2008;
doi:10.1152/japplphysiol.91008.2008

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Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and
muscle connective tissue in young women
M. Hansen, B. F. Miller, L. Holm, S. Doessing, S. G. Petersen, D. Skovgaard, J. Frystyk, A.
Flyvbjerg, S. Koskinen, J. Pingel, M. Kjaer and H. Langberg
J Appl Physiol 2009; 106 (4): 1435-1443.
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Invited Editorial
The mystery of female connective tissue
Michael Kjær and Mette Hansen
Institute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
FEMALES AND MALES DIFFER in many ways, including physiolog-
ically, and the fact that some types of connective tissue injuries
(e.g., ligament ruptures and bone stress fractures) are more
frequent in females than in males remains a puzzle. Estrogen
receptors are known to be present in fibroblasts of tendon and
ligaments. However, the effect of estrogen on anterior cruciate
ligament collagen turnover is still debated. In vitro studies have
reported an inhibiting effect, no effect, and a stimulating effect
on fibroblast proliferation and collagen synthesis (3). Never-
theless, animal findings and in vitro testing of human tendon
fascicles indicate that estradiol has a weakening effect on the
tissue (6). In humans it has been shown that females demon-
strate a lower collagen synthesis response to exercise than
males and also that the basal values for tendon collagen
synthesis were lower in females compared with males (5). This
suggests, but does not prove, that sex hormones could play a
regulatory role in collagen formation in tendon, collagen being
the most important load-bearing tissue in the matrix and the
most abundant protein in the human body.
In a study by Bryant et al. (1) in the Journal of Applied
Physiology, an interesting observation is made in humans,
namely that females who receive oral contraceptives with
synthetic estrogen and gestagens demonstrate stiffer Achil-
les tendons compared with matched women with normal
fluctuations in endogenous sex hormones. In the control
group, no variation in strain behavior of the tendon was
found with acute menstrual cycle fluctuations in hormones.
This indicates that long-term exposure to hormonal changes
alters the tissue structure and function, whereas short-term
variations do not. While not studied in the present study,
these findings may imply that the tendons of females receiv-
ing oral contraceptives have a thicker tendon fibril diameter,
which provides better ability for increased amounts of
intrafibrillar cross bindings and thus will result in an in-
creased stiffness of the tendon.
The study by Bryant et al. (1) therefore is suggestive of an
influence of female ovary hormones, e.g., estradiol, on the
collagen turnover of ligament and tendon tissue in humans.
This finding fits nicely with a recent observation that oral
contraceptives given to young women result in a reduced
response of exercise-induced tendon collagen synthesis (2),
and thereby indicates an inhibiting effect of oral contraceptives
containing synthetic estradiol. In that study, long-term admin-
istration of oral contraceptives was not associated with any
change in tendon diameter, suggesting that structural changes
in the tendon as a result of oral contraceptives are occurring in
the absence of any change in gross magnitude of the tendon.
Interestingly, the latter observation might be linked to cross-
sectional data, which have not shown any difference in gross
magnitude of Achilles and patellar tendons between trained
Address for reprint requests and other correspondence: M. Kjær, Institute of
Sports Medicine, Bispebjerg Hospital, Univ. of Copenhagen, DK-2400 Copen-
hagen NV, Denmark (e-mail: m.kjaer@mfi.ku.dk).
1026 8750-7587/08 $8.00 Copyright © 2008 the American Physiological Society
J Appl Physiol 105: 1026 –1027, 2008;
doi:10.1152/japplphysiol.91008.2008.
and untrained females, an observation that differs from find-
ings in males, where trained individuals demonstrate larger
tendons than untrained (4, 7). These observations further indi-
cate a sex-specific adaptation of tendon tissue and is suggestive
for estradiol playing an important role.
Recently, studies from our laboratory also have shown an
impaired tendon collagen synthesis response to exercise
when estrogen was raised in elderly women by estrogen
replacement therapy but that estrogen in the resting state if
anything had a stimulating effect on basal tendon collagen
synthesis (unpublished observations). Similarly, in young
women, a positive association between endogenous estra-
diol and tendon collagen synthesis at rest has been observed.
Downloaded from jap.physiology.org on March 23, 2011
For the resting state, this is in some contrast to the overall
suppressing effect that oral contraceptives have and may
suggest that endogenous estrogen has a “homeostatic effect”
on collagen synthesis, by having a pivotal role in stimulat-
ing collagen synthesis at rest but diminishing the exercise
response. Oral contraceptives, on the other hand, may have
an overall depressing effect on collagen synthesis. Whereas
these findings could indicate that women adapt slower than
males to training and therefore should take this into account
in designing their training programs in order not to increase
the incidence of injuries, it could be very likely that in the
reverse situation, during inactivity or bed rest, women are
more resistant to losing too much of their supportive struc-
ture during periods with lack of activity. By maintaining
homeostasis, women may be more robust toward detrimen-
tal perturbations, ensuring that vital female functions like
pregnancy and birth can be carried out without problems due
to pronounced changes in connective tissue properties.
The final question still remains to be solved, and that is
the mechanism by which sex differences in collagen tissue
adaptations occur, and while estrogen is one likely candi-
date, it is still not proven as to whether this effect is a direct
one or, rather, is mediated via other factors. Interestingly, it
has in recent studies been shown that administration of
synthetic estradiol is inversely related to the bioavailability
of free IGF-I in the peritendinous fluid surrounding the
tendon (2), and low estradiol may via elevated IGF-I stim-
ulate collagen formation in tendon. Local IGF-I is able to
stimulate connective tissue formation, and it is very likely
that female sex hormones play important roles in the inter-
play between growth factor in order to interact with me-
chanical loading, and thereby to regulate collagen synthesis
and to optimize the adaptation of tendon tissue in humans
with the major goal of avoiding sports injury and allowing
for optimal performance in both sexes.
REFERENCES
1. Bryant AL, Clark RA, Batold S, Murphy A, Bennell KL, Hohmann E,
Marshall-Gradisnik S, Payne G, Crossley KM. Effects of estrogen on the
mechanical behavior of the human Achilles tendon in vivo. J Appl Physiol
(June 19, 2008). doi:10.1152/japplphysiol.01281.2007.
http://www. jap.org

2. Hansen M, Koskinen SO, Petersen SG, Doessing S, Frystyk J, Flyvb-
jerg A, Westh E, Magnusson SP, Kjaer M, Langberg H. Ethinyl
estradiol administration suppress synthesis of collagen in tendon in re-
sponse to exercise in women. J Physiol 586: 3005–3016, 2008.
3. Lee CY, Liu X, Smith CL, Zhang X, Hsu HC, Wang DY, Luo ZP. The
combined regulation of estrogen and cyclic tension on fibroblast biosyn-
thesis derived from anterior cruciate ligament. Matrix Biol 23: 323–329,
2004.
4. Magnusson SP, Narici MV, Maganaris CN, Kjaer M. Human tendon
behaviour and adaptation, in vivo. J Physiol 586: 71– 81, 2008.
J Appl Physiol • VOL 105 • OCTOBER 2008 •
Invited Editorial
1027
5. Miller BF, Hansen M, Olesen JL, Schwarz P, Babraj JA, Smith K,
Rennie MJ, Kjaer M. Tendon collagen synthesis at rest and after exercise
in women. J Appl Physiol 102: 541–546, 2007.
6. Slauterbeck J, Clevenger C, Lundberg W, Burchfield DM. Estrogen
level alters the failure load of the rabbit anterior cruciate ligament. J Orthop
Res 17: 405– 408, 1999.
7. Westh E, Kongsgaard M, Bojsen-Møller Aagaard P, Hansen M, Kjaer
M, Magnusson SP. Effect of habitual exercise on the structural and
mechanical properties of human tendon, in vivo, in men and women. Scand
J Med Sci Sports 18: 23–30, 2008.
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