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Nandrolone Decanoate and Physical EffortHistological and Morphometrical Assessment in Adult Rat Uterus.

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THE ANATOMICAL RECORD 294:335–341 (2011)
Nandrolone Decanoate and Physical
Effort: Histological and Morphometrical
Assessment in Adult Rat Uterus
LUIZ GUSTAVO DE ALMEIDA CHUFFA,1* ROBERTA BARREIROS DE SOUZA,1
FERNANDO FREI,2 SUZANA DE FÁTIMA PACCOLA MESQUITA,3
1
AND ISABEL CRISTINA CHERICI CAMARGO
1
Department of Biological Sciences, Faculty of Sciences and Letters,
Paulista State University (UNESP), Assis, São Paulo, Brazil
2
Department of Experimental Psychology, Faculty of Sciences and Letters,
Paulista State University (UNESP), Assis, São Paulo, Brazil
3
Department of General Biology, State University of Londrina (UEL),
Londrina, Paraná, Brazil
ABSTRACT
In the past decades, the therapeutic use of anabolic androgenic steroids
(AAS) has been overshadowed by illicit abuse of these drugs by athletes and
non-athletes. Since that AAS can affect the reproductive tract, resulting in
reproduction and fertilization damages, the purpose of this study was to
investigate the nandrolone decanoate (ND) effects, associated or not with
physical effort, on the uterine histomorphometric parameters. Female Wistar
rats, sedentary or not, were exposed to treatment with ND by intraperitoneal injection (5 mg/kg/day, once a week) during four consecutive weeks.
Control animals, sedentary or not, received vehicle alone (propylene glycol)
in the same manner. The physical activity was forced swimming (20 min/
day). During the experiment, all animals were monitored by daily vaginal
smears. After 30 days of treatment, the females were sacrificed and their
uteri collected and examined under light microscopy techniques. The NDtreated females showed estrus acyclicity and decreased thickness of both the
epithelium and endometrial stroma. A reduction in the number and size of
blood vessels was also found in ND-treated rats submitted to physical effort
when compared to ND sedentary rats. ND-treated rats, regardless of exercise, exhibited stromal fibrosis and reduced gland ducts that displayed high
mitotic activity. A remarkable widespread presence of leukocytes occurred in
rats receiving ND and submitted to exercise. These results suggest that ND
associated or not with physical effort causes histomorphometric changes to
C 2010 Wiley-Liss, Inc.
the rat uterus. Anat Rec, 294:335–341, 2011. V
Key words: nandrolone decanoate; steroids; uterus; histology;
exercise; rat
Anabolic androgenic steroids (AAS) can be useful adjuvant therapy for refractory anemia, hereditary angioedema, breast cancer, and starvation status (Clark et al.,
1997), as well as for the treatment of hypogonadism, as
they stimulate sexual development (Wilson and Griffin,
1980). AAS, including testosterone and its synthetic analogues have also been used by healthy adolescents and
adults, athletes and nonathletes to increase muscle
mass, strength and physical dexterity (Iriart and
Andrade, 2002). It is estimated that there are over 45
C 2010 WILEY-LISS, INC.
V
Grant sponsor: Fundação de Amparo à Pesquisa do Estado de
São Paulo (FAPESP), Brazil.
*Correspondence to: Luiz Gustavo de Almeida Chuffa,
Department of Biological Sciences, Paulista State University
(UNESP), P.O. Box 19.806.900, Assis, SP, Brazil. Fax: (18) 33025848. E-mail: guchuffa@yahoo.com.br
Received 22 July 2009; Accepted 9 October 2010
DOI 10.1002/ar.21314
Published online 16 December 2010 in Wiley Online Library
(wileyonlinelibrary.com).
336
DE ALMEIDA CHUFFA ET AL.
anabolic steroid compounds available for abusive consumption by athletes, and in the past few years, their
use has increased among male and female subjects
(Lane and Connor, 1994; Bishop, 2005; Biden, 2006).
Recently, a comparative study involving American
teenager girls has suggested that several reports about
AAS administration have been inflated by false-positive
responses because of confusion with other supplementary compounds (Kanayama et al., 2007). According to
Hickson et al. (1989), steroids use is associated with
temporary or permanent adverse effects, which may
appear within weeks (e.g., altered reproductive function)
or require up to several years (e.g., liver carcinoma).
Administration of AAS by women is associated with
certain androgenic effects such as facial hair growth,
deepening of the voice, clitoral enlargement, and menstrual irregularities (Strauss et al., 1985; Korkia and
Stimson, 1997). Moreover, some disturbances in gonadal
function such as delayed puberty, luteal phase deficiency,
oligo-amenorrhea, or anovulation may occur in girls and
women participating in strenuous physical exercise
(Cannavò et al., 2001).
In fact, the short-term effects of AAS consumption,
associated or not with physical effort, on the female
reproduction is still an unsolved issue. Some studies
have reported the steroids effects on behavior (Gruber
and Pope, 2000; Elliot et al., 2007) and physiological
characteristics such as sexual receptivity and vaginal
cytology (Clark et al., 1998). Previous studies in our laboratory have shown that AAS treatment suppresses
estral cyclicity, leading to follicular atresia and absence
of corpora lutea (Gerez et al., 2005; Camargo et al.,
2009). It has also been observed some vacuolated epithelial cells and stromal fibrosis. In other experimental
study, administration of AAS to cynomolgus macaques
revealed increase in uterine weight and endometrial
thickness, as well as adenomyosis-like alterations and
incidence of mucometra (Obasanjo et al., 1998). Recently,
Kramer and McDonald (2006) proposed a causal relationship between athletic activity and sexual dysfunction, and it was ascribed to aerobic exercise and its
adverse effects on pregnancy outcomes and hypothalamic disturbances, which may result in cyclicity disruption (Warren and Perlroth, 2001). Additionally, maternal
exercise seems to be associated with the onset of hypertension or intrauterine growth restriction (Clapp, 2003;
Davies et al., 2003), which can be detrimental to uterine
function. Accordingly, the aim of this study was to verify
the effects of nandrolone decanoate (ND), associated or
not with physical effort, on morphologic and morphometric parameters in adult rat uterus.
MATERIALS AND METHODS
Animals and Experimental Design
Twenty adult female Wistar rats (Rattus norvegicus
albinus), 90 days old, were obtained from the Universidade Estadual Paulista (UNESP, Botucatu, SP, Brazil)
and kept at the Faculty of Sciences and Letters (UNESP,
Assis, SP, Brazil). The females were weighed and randomly divided into four experimental groups (N ¼ 5/
group): (1) C þ S: sedentary animals that received only
vehicle; (2) C þ E: animals that received vehicle and submitted to physical effort; (3) ND þ S: sedentary animals
treated with anabolic steroid; (4) ND þ E: animals treated
with anabolic steroid and submitted to physical effort. All
animals were housed in polypropylene cages (43 cm 30
cm 15 cm) with laboratory-grade pine shavings as bedding and also maintained under controlled room temperature (23 C 1 C) and lighting conditions (12L, 12D
photoperiod, lights switched on at 6 AM).
ND (4-estren-17B-ol-3-one 17-decanoate) was purchased from Organon Industry (São Paulo, Brazil) as an
injectable solution, containing 50 mg of the androgen.
The treated females received doses of ND (5 mg/kg BW
of Deca Durabolin), available as oily solution (Pope and
Katz, 1988; Marqueti et al., 2010). The doses were given
once a week via intraperitoneal injection (KarbalayDoust and Noorafshan, 2009), during four consecutive
weeks. In this study, this dosage and administration
schedule deals the same condition of AAS users found at
fitness centers. Thus, ND injection was administrated on
the same day (Wednesday) and at the same time (11:30
AM) to keep the estrous condition. The control groups
received 0.5 mL of the propylene glycol as vehicle solution, according to the same procedure applied to the
treated groups. All animals received tap water and
commercial NuvitalV chow ad libitum.
As forced-exercise can cause forefoot and toe injuries
because of the impact and stress arising from the exercise
models, aerobic swimming was chosen as the method of
physical effort, in accordance with Peres and Luciano
(1995). The rats were conditioned to the exercise before
the beginning of the experimental period, starting with 5
min/day for the first 2 days, then 10 min on the third and
fourth days, followed by 15 min on the fifth and sixth
days, and 20 min on the seventh day. After this period,
the scheme of 20 min to swimming was daily taken, during five consecutive days per week. Following 30 days and
24 hr after the last injection, all animals were killed by
decapitation. The experimental protocol followed the ethical principles in animal research adopted by the Brazilian
College of Animal Experimentation.
R
Light Microscopy
The estral cycle was daily monitored by vaginal smear
cytology, as previously described by Marcondes et al.
(2002) and Chuffa et al. (2009). The female rats exhibiting regular or irregular estrous cycle were killed, and
their ovaries, uterus, and hypophysis were collected and
weighed. The uterine horns were fixed in Bouin’s solution and processed by the usual histological routine
for paraffin embedding (Paraplast Labware-Oxford,
St.Louis, MO). The blocks were sliced into 5-lm-thick
sections in a LEICA microtome and stained with Hematoxilin-Eosin (H&E) and Mallory’s Tricromic. Histological samples of uterine horns were handled in a blinded
fashion study. Finally, the slides were analyzed and captured with a digital photomicroscope.
Morphometric Measurements
For morphometric analysis of uterine layers, one
section was selected and five consecutive others were
discarded, until the last section of the organ, resulting
in 10 repetitions/rat/group (50 measures/group). Five
micrometer sections of uterine epithelium, endometrial
stroma, myometrium, and perimetrium were evaluated
in the proximal, middle, and distal portions of uterus,
337
STEROID AND HISTOMORPHOMETRY OF UTERUS
TABLE 1. Data of body weight (g), ovaries and uterus weights (g/100 g body weight), and hypophysis
weight (g) in female rats receiving ND and submitted or not to physical effort
Groups
CþS
Parameters
Body
Ovaries
Uterus
Hypophysis
236
0.110
0.548
0.011
CþE
1.0
0.084
0.025
0.001
237
0.103
0.450
0.011
ND þ S
9.0
0.001
0.014
0.031
274
0.099
0.364
0.009
1.0
0.023
0.100a
0.095a
ND þ E
247
0.099
0.445
0.008
1.0
0.020
0.052
0.109b
Values are expressed as median interquartile deviation.
In the same line, median with letters show statistical differences among the groups (P < 0.05). Kruskal-Wallis with posthoc Dunn test.
a
P < 0.05 Significant difference from C þ S group.
b
P < 0.05 Significant difference from C þ E group.
TABLE 2. Morphometric parameters (Mean 6 SD) regarding to three distinct
uterine layers among the groups
Groups
Parameters
Thickness
PP
MP
DP
Thickness
PP
MP
DP
Thickness
PP
MP
DP
Thickness
PP
MP
DP
of uterine epithelium
of endometrial stroma
of myometrium
of perimetrium
CþS
CþE
ND þ S
ND þ E
27.45 5.52
32.05 7.22
23.85 1.98
30.80 6.81
29.80 6.98
29.30 2.08a,c
19.80 1.27a
19.75 2.08a
20.10 3.70
18.30 1.77b
17.20 3.05b
17.95 1.85
532.85 48.75
579.30 112.20
584.05 132.07
661.70 59.05a
638.50 158.00
634.20 128.43
342.75 48.88a
402.15 79.55a
356.00 74.00a
335.20 37.04b
334.05 69.68b
400.45 91.95b
342.95 92.44
327.40 68.91
336.50 69.45
342.95 87.02
416.90 92.22a
422.20 48.70a
326.95 74.22
432.95 87.00a
380.40 74.55
259.10 95.97b,d
300.40 71.24b,d
332.50 40.40b
11.15 1.58
10.20 2.90
11.30 2.02
12.60 3.00
11.55 2.45
12.30 3.75
14.95 3.02a
15.05 1.40a
14.30 3.08a
14.40 2.81
14.30 2.05b
14.95 2.99b
PP, MP, and DP ¼ proximal, middle, and distal portion of uterine horn were determined according to ovary position, respectively. Values are expressed using 10 repetitions (lm 10)/animal/group.
Letters indicate statistical differences among the groups (P < 0.05). ANOVA test complemented by Newman-Keuls.
a
P < 0.05 versus C þ S group.
b
P < 0.05 versus C þ E group.
c
P < 0.05 versus ND þ E group.
d
P < 0.05 versus ND þ S group.
relative to the position of the oviduct and ovary. The
thickness of epithelium was measured on the endometrial surface, and the stromal thickness was obtained by
tracing around the on-screen image with a cursor considering repeated measurements in both basal and functional layers (Rossi et al., 2002). Values were taken as
the total uterine cross-sectional area. The endometrial
glands were not measured. The blood vessels parameters
were taken within the predetermined and fixed 1 mm2
area. Thereafter, all the measures, including major or
minor diameter as well as the respective areas, were
performed randomly with the same slices and following
the same criteria (cross-sections) used to determine the
thickness of uterine layers. The trials were carried out
using the computerized image analysis system Image
R (Media Cybernetics) at 100 magnification.
Pro-PlusV
Statistical Analysis
Body weight data and ovaries, uterus, and hypophysis
weights were determined by the nonparametric Kruskal-
Wallis test, complemented by Dunn, and the results
were expressed as median interquartile deviation. All
histomorphometric data were performed by ANOVA,
complemented by Newman-Keuls or Tukey tests, and
the results were given as mean SD. Statistical significance was set at P < 0.05. The statistical software used
was Sigma Plot version 11.0 and GraphPad Instat version 4.
RESULTS
After 4 weeks of treatment, there were no significant
differences (P > 0.05) in body weight and ovary weight
among the experimental groups (Table 1), however, in
animals treated with ND, the uterine horn weight was
reduced compared to the sedentary control group. NDtreated rats, whether submitted or not to physical effort,
presented significantly (P < 0.05) lower hypophysis
weight than the control groups (Table 1). Vaginal cytology examination revealed that both sedentary and
trained control groups presented regular estrous cycles
during the experimental period, while the ND-treated
338
DE ALMEIDA CHUFFA ET AL.
TABLE 3. Morphometric analysis of blood vessels throughout the myometrial layer
Groups
Parameters
Number of blood vessels (mm2)
Major/minor diameter (mm2)
Blood vessels area (mm2)
CþS
21.11
46.92
45.15
22.46
2.73
1.29
1.89
1.44
CþE
19.20
44.29
42.47
21.11
0.74
1.46
1.70
1.28
ND þ S
14.30
26.13
23.18
15.97
1.70a,b
2.48a
1.98a
0.90a
ND þ E
8.67
22.22
21.31
19.45
0.90c
1.43c
1.32c
0.77d
Values are expressed as Mean SD.
Letters indicate statistical differences among the groups (P < 0.05). ANOVA test complemented by Tukey-Krammer.
a
P < 0.01 implicate significant difference from C þ S group.
b
P < 0.01 implicate significant difference from ND þ E group.
c
P < 0.01 implicate significant difference from C þ E group.
d
P < 0.01 implicate significant difference from ND þ S group.
groups showed persistent metaestrous phases, which
was classified as the onset of anovulation.
Morphometric data demonstrated that in ND-treated
groups, the thickness of uterine epithelium and endometrial stroma were significantly reduced (P < 0.05) in the
proximal and middle portions (Table 2) compared to the
control groups, regardless of exercise. The myometrial
layer exhibited variations in thickness. In non-sedentary
ND-treated rats, the myometrial layer was reduced in
all portions. Although the exercise did not affect the
perimetrium, this layer was significantly (P < 0.05)
thicker in the uterus of ND-treated rats (middle and distal portions) than in control groups.
ND-treated rats, submitted or not to exercise, had a
reduction in the number of blood vessels around the
myometrium, with the most prominent effect (P < 0.001)
being found in ND þ E group (Table 3). Regarding blood
vessels properties, the major and minor diameter was
significantly lower in both ND-treated groups than nontreated groups, showing that this effect is because of
treatment and not to exercise. Blood vessel area was
more restricted in ND-treated rats than in control group,
however, ND þ E rats evidenced a greater blood vessel
area than those receiving only ND (Table 3).
The females of control groups, submitted or not to
exercise (Fig. 1A–C), presented a uterine lumen lining
consisting of high columnar epithelial cells, with nuclei
localized at different levels and no mitotic activity. Fragments of degenerating cells were more evident in C þ E
than C þ S group, which were recognized in the epithelium by the presence of pyknotic nuclei and fragmented
chromatin (Fig. 1C). Furthermore, stromal tissue presented a loose aspect, with slightly tortuous glands (Fig.
1B). In ND-treated females (Fig. 1D,E) were found a
thin uterine epithelium shaped by cubic cells with
marked mitotic activity, especially in sedentary rats
(Fig. 1G). In addition, short and narrow glands were evidenced in a predominantly fibrous compact stroma (Fig.
1D–F) showing a large amount of widespread leucocytes
(Fig. 1E). The fibrous stroma was remarkable in NDtreated rats (Fig. 2B), in contrast to the edematous cellular stroma of the sedentary control group (Fig. 2A). On
the basis of transition layer from endometrium to myometrium, it was noted that large and small blood vessels
area were lower in ND-treated rats submitted to physical effort (Fig. 2C) than in ND þ S group (Fig. 2D),
showing only the effects of exercise. Finally, there was
no evidence of morphological impairment in the myometrium or perimetrium of ND-treated rats.
DISCUSSION
Exercise training decreases fat mass storages in male
and female rats (Estadella et al., 2004) as well as in
humans (Aull et al., 2008). In this regard, the exercise
model utilized in this experiment was not efficient to
decrease body weight. Despite of the well known anabolic
effect of ND, these rats showed decreased body weight,
although it was not statistically significant. The results
are in accordance with previous studies reported by Blasberg et al. (1997) and Clark et al. (2003). Studies involving
female rats (Gerez et al., 2005) and mice (Gao and Short,
1993) have found no differences among reproductive organ
weights in ND-treated animals; however, in the present
study, the uterine horn weights were reduced when compared to controls (Table 1). One possible explanation is the
direct or indirect ND effect on the uterus via hormonal
imbalances, and not the role of physical effort by itself.
Similarly, Bronson et al. (1996) reported that the ovary
and uterus weights are affected by steroid replacement.
The reduction of hypophysis weight in ND-treated rats are
in agreement with results obtained by Gao and Short
(1993), the only extant study reporting the role of ND and
its interaction with the hypophysis gland. However, to better understand these effects, further experiments involving
rat strains and different doses of AAS are required.
To the best of our knowledge, AAS are typically administrated under supraphysiological dose (megadoses) ranging from 3 mg/kg BW to 25 mg/kg BW to increase muscle
mass. These concentrations are reported to be 10- to 100fold higher than the therapeutic dose (Brower, 1993;
Clark and Fast, 1996). For example, according to Far
et al. (2007), a dose of 15 mg/kg BW corresponds to 40fold, the dose used to anaemia treatment. Thus, it should
be borne in mind that our dose of 5 mg/kg is almost 15fold higher than those used for such therapies, and it is
sufficient to produce failures in rat uterus.
According to Feinberg et al. (1997), the synthetic steroids alter the function of hypothalamic-pituitary-gonadal axis, thus indirectly affecting the reproductive
tissues. In this condition, the estrous cycle disruptions
in ND-treated females may be attributed to hormone interference caused by ND. Our findings are similar to the
results obtained by Howe and Morello (1985); Gao and
Short (1993); and Bronson et al. (1996). It should be
emphasized that regular physical activity is related to
higher levels of anabolic hormones in adults (Copeland,
2004). Blasberg et al. (1997) found that rats receiving
5.6 mg/kg of ND exhibited lordosis behavior accompanied by interrupted vaginal cyclicity because of
STEROID AND HISTOMORPHOMETRY OF UTERUS
339
Fig. 1. Photomicrographs of uterine morphology (middle portion). In
C þ S group (A) and C þ E group (B), note the high columnar epithelium (ep) and the stroma (st) with loose aspect. In (B), a slightly tortuous
gland (*) in edematous stromal tissue is also evidenced; Bar ¼ 30 lm.
(C) Fragmented chromatin (arrow) surrounding the epithelium was remarkable in C þ E rats; Bar ¼ 30 lm. In ND þ S and ND þ E groups
(D–F), the reduced uterine epithelium (ep) with a thin aspect is shown.
Stromal fibrosis (st) was only prominent in those rats that received both
ND and exercise. In (E), scarce leucocytes were present around the
blood vessels of endometrial stroma. The uterine epithelium featured
several cell divisions (arrow) in ND-treated rats in the absence of exercise (G). Bar ¼ 30 lm. G: uterine glands, L: leucocytes, M: epithelial
metaplasia. Hematoxylin-Eosin. For all details; Bar ¼ 10 lm.
persistent diestrous phases. Knowing that the bioconversion of AAS to estrogens may influence estrous cyclicity
by altering aromatase activity (Friedl and Yesalis, 1989),
these enhanced estrogenic/antiestrogenic effects could,
at least in part, explain the changes in cyclicity and
uterine morphology observed in our study.
Regarding uterine blood circulation, all trained and
ND-treated rats presented a reduction in the number and
diameter of blood vessels throughout the myometrium
layer. It seems reasonable to consider that during exhaustive exercise, blood flow is preferentially delivered to skeletal muscle, allowing only a small fraction available to
visceral smooth muscles (Rowell, 1993), a phenomenon
also observed in rats by Dowell and Kauer (1993). Thus,
our findings can be partially supported by the strenuous
exercise. Also, in pregnant women, long-term exercise at
moderate/high intensity leads to decreased uterine blood
flow (Clapp et al., 2000; Jeffreys et al., 2006).
340
DE ALMEIDA CHUFFA ET AL.
Fig. 2. Morphology of the uterine layer in control and ND-treated
rats, submitted or not to physical effort. In (A), note the slightly edematous stroma (*) with scattered leucocytes. In ND þ E group (B), fibrous stroma (*) with narrow uterine glands (G) and blood vessels (BV)
are prominent. Regarding the inner muscle layer of the myometrium,
the blood vessels (arrow) of ND þ E rats (C) displayed a reduction in
both number and diameter in contrast to ND þ S rats (D); ep: uterine
epithelium, L: leukocytes, M: myometrium, P: perimetrium. Mallory’s
Trichrome. Bar ¼ 20 lm.
As previously stated, histological and morphometric
changes pointed to endometrial atrophy (Table 2, Fig.
1D,E), indicating that uterine layers are quite responsive
to AAS treatment. Similarly, supraphysiological doses of
ND (15 mg/kg) led to alterations in the uterine morphology, such as endometrial atrophy and glands with tortuous and irregular branching (Far et al., 2007). Taking
into account that androgenic receptor (AR) is expressed in
both endometrium and myometrium and regulates the
proliferative response to ND (Mertens et al., 1996), we
conclude that this atrophy was promoted by the maintenance of metaestrus phase (depletion of estrogen levels)
induced by the treatment. The appearance of leukocytes
infiltrated into the endometrial stroma of ND þ E group
was also clearly observed. It is well known that leukocytes are recruited by the uterus and undergo changes
depending on estrous phase, which in turn is regulated
by levels of steroids such as estrogen and progesterone
(Kaeoket et al., 2001). In this context, the ND treatment
could change the steroidal levels resulting in estrous disruption, which is associated with the presence of these
cells. In the current study, the thickening of the perimetrium layer suggests an attempt to restore the composition of the uterus and, conversely, AAS treatment had no
effect on this parameter, regardless of physical effort. In
ND-treated females, the most evident morphological
changes were the presence of a thin luminal epithelium
and the fibrous stroma. There are several studies focusing
uterus alterations and its consequences to reproduction;
however, it is not a consensus when related to androgen
responsiveness. Thereby, other results obtained by YuYahiro et al. (1989) reported that treatment with ND
promoted epithelial vacuolization, stromal edema, and
peliosis in rat uteri. In contrast, Gerez et al. (2005) has
assigned substantial fibrosis on the endometrial stroma
and some epithelial vacuolization in females treated with
ND. Curiously, a recent study has demonstrated that
replacement therapy with estradiol (E2) is directly related
to stromal fibrosis (Wood et al., 2010). Thus, we could
explain partially these findings, as a part of AAS is converted to estrogen by aromatase activity. Nevertheless,
the exact mechanism by which ND histomorphologically
affects the uterus remains unclear.
In conclusion, our findings suggest that ND has a different pattern of response in female rats, independent to the
physical effort. Moreover, ND promotes histomorphometric
changes to the uterine structure of adult female rats.
ACKNOWLEDGMENTS
The authors thank Mrs. Maria Isabel de Oliveira from
the Department of Biological Sciences, for her technical
assistance.
STEROID AND HISTOMORPHOMETRY OF UTERUS
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