JOURNAL OF MEDICINAL FOOD

J Med Food 22 (6) 2019, 631–638

# Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2018.0160

Soy Intake Since the Prepubertal Age May Contribute to the Pathogenesis
of Endometriosis in Adulthood
Marie Alfrede Mvondo,1 Jessica Darelle Ekenfack,1 Stéphane Minko Essono,1 Harding Saah Namekong,1
Charline Florence Awounfack,2 Matthias W. Laschke,3 and Dieudonné Njamen2
1
Research Unit of Animal Physiology and Phytopharmacology, University of Dschang, Dschang, Cameroon.
2
Laboratory of Animal Physiology, University of Yaounde 1, Yaounde, Cameroon.
3
Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany.

ABSTRACT High prevalence of endometriosis was reported in Asian women as a result of their traditionally high intake of
soy foods during infancy. Soy is widely used in infant feeding after weaning from breast milk or cow milk. This study thus
aimed to determine to what extent soy intake before puberty may contribute to the development of endometriosis. For this
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purpose, immature (6-week old) female rats were fed with various soy formulas (0%, 10%, 20%, 30%, 40%, 50%, and 60%).
Normal control animals were fed with a soy-free diet. At 13 weeks of age, animals (except the normal control) underwent a
transplantation surgery to establish endometriosis. Estradiol valerate and oxytocin were used to induce pelvic pain. En-
dometrial implant levels of glutathione (GSH) and malondialdehyde (MDA) allowed estimating tissue oxidative status.
Physiological ovarian function was assessed by histological analysis of ovaries. Results showed that soy-fed animals grew
faster than animals receiving a soy-free diet (P < .001). In animals supplemented with more than 10% of soy, the intensity of
pelvic pain increased (P < .001) as well as the volume of ectopic foci. In addition, tissue levels of MDA and GSH increased
(P < .001). The ovarian function was altered and the number of luteinized unruptured follicles increased. In conclusion,
although animals supplemented with soy at the prepubertal stage displayed a good growth performance, regular soy con-
sumption may promote the development and progress of endometriosis in adulthood, especially when soy content in food is
more than 10%.

KEYWORDS:  endometriosis  ovarian function  rat  soy-based formula

INTRODUCTION of them develop endometriosis in their reproductive age,2

suggesting the involvement of other factors in the patho-

E ndometriosis is a gynecological disease charac-

terized by the presence of functional endometrial tissue
outside the uterine cavity, most often in the peritoneal cav-
ity.1 Its prevalence is estimated to *10% of women in their
reproductive years,2 25–40% of infertile women,3 and 71–
87% of women with chronic pelvic pain.4
The most well-accepted theory to explain the develop-
ment and progression of peritoneal endometriotic lesions is
retrograde menstruation. According to this theory, endo-
metrial cells are refluxed, during menses, through the fal-
lopian tubes and attached to pelvic or peritoneal organs.5
Very quickly, these endometrial fragments initiate angio-
genesis to establish an adequate blood supply for the sur-
vival of endometriotic lesions.6 Retrograde menstruation is
reported to occur in almost all women,5 but only about 10%
Manuscript received 8 October 2018. Revision accepted 28 January 2019.
Address correspondence to: Marie Alfrede Mvondo, PhD, Research Unit of Animal Phy-
siology and Phytopharmacology, University of Dschang, P.O Box 67, 00237 Dschang,
Cameroon. E-mail: mvondo.mariealfrede@yahoo.com; alfrede.mvondo@univ-dschang.org
genesis of endometriosis.
Physiological and pathological processes of endometri-
osis are thought to be influenced by dietary estrogens.7 The
highest human exposure to these biologically active sub-
stances is reported to occur in infants fed soy-based infant
formula.8 Soy products contain high quantities of phytoes-
trogens, predominantly the isoflavones genistein and daid-
zein, which are structurally similar to estradiol and can
interact with estrogen receptors.8,9 Exposure to these sub-
stances during infancy is suspected to increase the incidence
of endometriosis in adulthood.8 The literature reports a high
prevalence of endometriosis in Asian women10 as a result of
their traditionally high intake of soy foods, especially during
infancy.7,10 In developing countries, especially in Africa,
soy formulas (SF) are commonly fed to infants as a re-
placement for human milk or cow milk9 to prevent malnu-
trition. Given the importance of soy supplementation in
infant nutrition,9 it seems necessary to determine to what
extent soy intake before puberty may contribute to the de-
velopment of endometriosis.

631
 632 MVONDO ET AL.
To address this question, immature female Wistar rats
were fed with a range of SF. In adulthood, they underwent a
transplantation surgery to establish endometriosis. Animals
with endometriosis were used to investigate the effects of a
daily consumption of SF on endometriosis and some related
ailments, especially pelvic pain and altered ovarian function
(this refers to follicle development, ovulation, formation,
and regression of the corpora lutea).11
MATERIALS AND METHODS
Soybeans and preparation of SF
Dry soybeans (Glycine max (L.) Merr. (Fabaceae)) were
purchased in Dschang food market (Cameroon) and identi-
fied at the Cameroon National Herbarium, where a specimen
has been deposited under the number 42641/HNC.
Soybeans were roasted over low heat till they became
crispy. Roasted soybeans were ground and the resulted flour
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was used for the preparation of SF. Each formula consisted
essentially of a standard soy-free diet. Roasted soybean flour
was added to this diet in proportions ranging from 0%
(SF0%) to 60% (SF60%).
Animals
Female Wistar rats 4 weeks of age were obtained from the
breeding facility of the Research Unit of Animal Physiology
and Phytopharmacology, University of Dschang (Camer-
oon). All rats had free access to diet and water ad libitum.
Animal handling and in vivo experiments were carried out in
conformity with the European Union on Animal Care (CEE
Council 86/609) guidelines adopted by the Institutional
Ethics Committee of the Cameroon Ministry of Scientific
Research and Technology Innovation.
Study design
After being weaned from breastfeeding, 4-week-old fe-
male rats were bred and kept under a standard soy-free diet.
Two weeks after acclimatization, animals were randomly
distributed into eight groups of seven animals each: sham
and negative control groups were fed with a soy-free diet
(SF 0%) and the six remaining groups received food for-
mulations containing proportions of soy ranging from 10%
to 60%, respectively. Seven weeks later, animals 13 weeks
of age underwent a transplantation surgery to establish en-
dometriosis, except sham-operated animals, as previously
described.11,12 Four weeks later, animals underwent an ex-
ploratory laparotomy to examine if peritoneal endometriotic
lesions had been successfully established and to determine
their volume as previously described.11,12 After a recovery
period of 28 days, each rat in the estrus phase received an
intraperitoneal injection of oxytocin (2IU/rat) to induce
writhing responses. Thirty minutes after observing the
writhing responses, animals were sacrificed under anesthe-
sia. Ectopic foci were excised and homogenated in 10 mM
Tris (tris(hydroxymethyl)aminomethane) buffer (0.1 g per
1 mL). Tissue homogenates were centrifuged at 1408 g for
10 min at 5C. The resulting supernatants were stored at
-20C till use. The uterus and the right ovary of each animal
were collected, cleaned of fat tissues, weighed, and fixed in
10% formalin for histological analysis. Animal body weight
was recorded weekly from the beginning to the end of the
study.
Biochemical analysis
Glutathione (GSH) levels were determined by the method
of Sehirli et al.13 Tissue levels of GSH were determined as
follows: [GSH] = DDO/e $ L $ m
Malondialdehyde (MDA) levels were determined by the
method of Wilbur et al.14 and their levels in tissue homog-
enates were determined as follows: [MDA] = DDO/e $ L $ m
DDO is the absorbance of the sample—absorbance of the
reagent blank and e is the molar extinction coefficient. It is
equal to 1.56 · 10–4 nM-1 cm-1 for MDA and 1.36 · 10–5
nM-1. cm-1 for GSH; L is the path length (1 cm) and m is the
mass of the tissue collected for homogenization (mg).
Histological analysis
Histological analyses of the ovaries and uterus were as-
sessed from 5-lm sections of paraffin-embedded tissues.
Following hematoxylin-eosin staining, the uterine epithelial
height was assessed on microphotographs using the com-
plete Zeiss equipment consisting of a microscope Axioskop
40 connected to a computer where the image was transferred
and analyzed with the MRGrab1.0 and Axio Vision 3.1
software, all provided by Zeiss (Hallbergmoos, Germany).
Ovarian follicles were counted on four sections of the same
ovary by two investigators and the final result for each ovary
represents the mean of the two observations. Luteinized
unruptured follicles (LUFs) were identified by the presence
of oocytes not surrounded by cumulus oophorus cells within
mature antral follicles.11,15
Statistical analysis
Data were analyzed using the GraphPad Prism 5.03
software. One-way analysis of the variance (ANOVA) fol-
lowed by the Tukey post hoc test for multiple comparisons
were used for the analysis of data with one variable (soy-
based formulations). ANOVA repeated measures followed
by the Bonferroni post hoc test for multiple comparisons
were used to analyze data with two variables (time, soy-
based formulations). Data are presented as mean – standard
error of the mean (SEM). Differences were considered
significant at P < .05.
RESULTS
Body weight
The growth of animals in the control group [ENDO +
SF0%] was similar to that of sham-operated animals
throughout the study (Fig. 1A). Up to 4 weeks after the
beginning of the experiment, the weight of animals receiv-
ing soy-enriched diets was similar to that of animals
 A 250 SHAM + SF0% ENDO + SF0% B 250 ENDO + SF0% ENDO + SF10%
c
c
c ##
c
c ### ### ###
200 c 200 c ###
c c c
c ### ###

Body weight (g)

Body weight (g)
c c
###
c c
c c c c ### c c
c
c c c c ## ## c
150 c c c c 150 c
c c c c
c c c c
c c c c
c c c
c c c c c
100 c 100 c
c c
c
c c
50 50

0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Before endometriosis Following endometriosis Before endometriosis Following endometriosis

induction induction induction induction

Time (weeks) Time (weeks)

C 250 ENDO + SF0% ENDO + SF20%

c
c c
c ### ### D 250 ENDO + SF0% ENDO + SF30%
c c
c ### ###
c ### c c
c c c ### #
c ### c ### ### ##
200 200 ### ### ###
c c c ### c
Body weight (g)

Body weight (g)

c ###
### ### ### c
c c c c
c ### ### c c c
c ### c ### c
150 ## c 150 c
c c c c c c
###
c c c c
c c
### c c c
100 c 100 c c
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c c
c c
50 50

0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Before endometriosis Following endometriosis Before endometriosis Following endometriosis

induction induction induction induction

Time (weeks) Time (weeks)

E 250
ENDO + SF0% ENDO + SF40% F 250
ENDO + SF0% ENDO + SF50%
c c c c
c c
c ### c c
c c
c ### ### ## # # c
c c ### ### ### c #
200
200 c ###
### ### c ###
Body weight (g)
Body weight (g)

c c ###
c c c
c ### ### c c c ### c c
c c ## c
c ### 150
150 ### c c # c
c c ### c c
c c c c
c c c c c
100 c 100 c c c
c #
a c c
c c
50 c 50

0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Before endometriosis Following endometriosis Before endometriosis Following endometriosis

induction induction induction induction

Time (weeks) Time (weeks)

G 250 ENDO + SF0% ENDO + SF60%

c
c c
c c c c # ##
200 c ### ### ### #
c ###
Body weight (g)

c ###
### c
c c c
c # c
150 # c
c c c
###
c c
c c
100 c c

c
c
50

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Before endometriosis Following endometriosis

induction induction

Time (weeks)

FIG. 1. Growth performance in soy-free-fed animals (A) and in animals supplemented with 10% (B), 20% (C), 30% (D), 40% (E), 50% (F) and
60% (G) of soy. SHAM, sham-operated animals; ENDO, animals with endometriosis; SF, soy-based formula, data are presented as mean – SEM,
n = 7, aP < .05 and cP < .001 versus week 1, #P < .05, ##P < .01, and ###P < .001 versus SF0%.

633
 634 MVONDO ET AL.

receiving a soy-free diet. From week 5 to the end of the

study, the weight of soy-fed animals was greater (P < .001)
compared with the [ENDO + SF0%] group (Fig. 1B–G).

Endometriotic implant volume and tissue MDA

and GSH levels
The volume of endometriotic implants of animals in the
[ENDO + SF10%] group was similar to that of the [ENDO +
SF0%] group. In the other soy-fed animal groups, en-
dometriotic implant volumes increased at least by 54%
(Fig. 2A).
Tissue levels of MDA, as well as GSH, increased in all
soy-fed animals when compared to the [ENDO + SF0%]
group (Fig. 2B, C).

Writhing responses
Writhing frequency increased by twofold in animals of
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the [ENDO + SF0%] group compared to sham-operated

animals (Fig. 3A). In the [ENDO + SF10%] group, writhing
frequency decreased by 24% compared to the [ENDO +
SF0%] group. In the four other soy-fed animal groups, this
parameter rather increased significantly.
Writhing latency decreased by 72% (P < .01) in animals
of the [ENDO + SF0%] group compared to sham-operated
animals (Fig. 3B). In soy-fed animal groups, we observed a
kind of biphasic response: while writhing latency increased
by 75% and 25% in [ENDO + SF10%] and [ENDO +
SF20%] groups, respectively, it decreased by 6% in the
[ENDO + SF30%] group, 37% in the [ENDO + SF40%]
group, 29% in the [ENDO + SF50%] group, and 37% in the
[ENDO + SF60%] group.

Ovarian function
The number of antral follicles decreased by 57%
(P < .001) in the ovaries of animals in the [ENDO + SF0%]
group compared to sham-operated animals (Fig. 4A). In soy-
fed animals, the number of antral follicles was similar to that
of the [ENDO + SF0%] group.
LUFs were 2.67 times (P < .01) more elevated in animals
of the [ENDO + SF0%] group than in sham-operated ani-
mals (Fig. 4B). In almost all soy-fed animals, the number of
LUFs increased by at least 12% compared to the [ENDO +
SF0%] group.
The number of corpora lutea was 39% more elevated in
the [ENDO + SF0%] group than in sham-operated animals
(Fig. 4C). This parameter further increased in animals sup-
plemented with more than 10% of soy.

Relative uterine weight, uterine epithelial height, FIG. 2. Endometriotic implant volume (A) and tissue levels of
and histological score of the uterine epithelium MDA (B) and GSH (C). Data are presented as mean – SEM versus,
n = 7, #P < .05 and ###P < .001 versus [ENDO + SF0%]. GSH, gluta-
Figure 5A shows that the relative uterine weight of ani- thione; MDA, malondialdehyde.
mals in the [ENDO + SF0%] group was similar to that of
sham-operated animals. In all soy-fed animals, the relative
uterine weight significantly increased compared to the
[ENDO + SF0%] group.
 SOY INTAKE AND ENDOMETRIOSIS 635
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FIG. 3. Writhing responses: frequency (A) and latency (B). Data

are presented as mean – SEM, n = 7, *P < .05, **P < .01, and ***P < .001
versus [SHAM + SF0%], #P < .05, ##P < .01, and ###P < .01 versus
[ENDO + SF0%].

In the [ENDO + SF0%] group, the uterine epithelial

height was similar to that of sham-operated animals
(Fig. 5B). In comparison with the [ENDO + SF0%] group,
the uterine epithelial height increased at least by 23% in all
soy-fed animals.
The uterus of sham-operated animals was lined by a tall
columnar epithelium showing mitosis figures. Similar ob-
servations were made on the uterus of animals in the [ENDO
+ SF0%] group. In soy-fed animals, both mitosis and ne-
crosis figures were seen on the tall columnar uterine epi-
thelium (Fig. 6)

DISCUSSION
Despite the benefits attributed to soy with respect to
growth performance,16 as shown in this work, its regular
consumption since childhood was associated with an in-
creased incidence of endometriosis in adulthood.9 In this
study, we evaluated the effects of a range of soy-based
formulas on the development of endometriosis and some of
its related ailments in female Wistar rats exposed to soy
since the prepubertal age. Results showed that the volume of
endometriotic implants increased remarkably in animals
supplemented with more than 10% of soy, suggesting that at
FIG. 4. Number of antral follicles (A), luteinized unruptured fol-
licles (B), and corpora lutea (C) in rat ovaries. Data are presented
as mean – SEM, n = 7, *P < .05, **P < .01, and ***P < .001 versus
[SHAM + SF0%], ##P < .01, and ###P < .01 versus [ENDO + SF0%].
LUF, luteinized unruptured follicle.
more than 10%, soy supplementation since the prepubertal
age may facilitate and promote the survival and develop-
ment of ectopic foci. This increase in implant volume was
associated with an increased level of MDA, an end product
of lipid peroxidation. This result is consistent with previous
 636 MVONDO ET AL.
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FIG. 5. Relative uterine weight (A) and uterine epithelial height
(B). Data are presented as mean – SEM, n = 7, *P < .05 and
***P < .001 versus [SHAM + SF0%], #P < .05 and ###P < .01 versus
[ENDO + SF0%].
studies12,17 linking oxidative stress with the development of
endometriosis. Oxidative stress was reported to promote
angiogenesis and tumor development.18 The formation of
new blood vessels allows establishing an adequate blood
supply for the survival of endometriotic lesions.8 The in-
crease in GSH levels could be a response to the oxidative
activity prevailing in these lesions.
The growth of endometriotic implants, which are uterine
fragments, was also associated with prominent increase in
the relative uterine weight and a slight increase in the uterine
epithelial height. These estrogen receptor (ER) a-mediated
events19 are consistent with previous works reporting that
soy contains high quantities of ER agonists, especially
genistein,8,9 which was found to stimulate the expression of
water channels in the uterus of Wistar rats leading to uterine
hypertrophy.20 Furthermore, the histological analysis of the
uterine epithelium showed that, while the epithelium of soy-
free-fed animals were presenting mitosis figures, that of soy-
fed animals exhibited both mitosis and necrosis figures. The
literature reports that genistein, a soy-derived flavonoid, acts
both as a selective estrogen agonist and a selective estrogen
antagonist in the uterus of prepubertal rats,21,22 unlike
daidzein, another soy-derived flavonoid that was rather
found to potentiate estrogen-induced cell proliferation in rat
uterus.23 Treatment of prepubertal rats with genistein was
found to induce a hypertrophy of uterine epithelial cells, but
not cell proliferation.21 In addition, the pretreatment of
prepubertal rats with genistein resulted in a total inhibition
of estradiol-induced mitoses in uterine luminal epithelium.22
Therefore, the presence of both genistein and daidzein in
soy-enriched diets may explain at least, in part, the ap-
pearance of both mitosis and necrosis figures on the uterine
epithelium of soy-fed animals. Our results therefore suggest
that a daily consumption of diets containing more than 10%
of soy since the prepubertal age may have promoted the
development of endometriosis by promoting tissue oxida-
tive stress and cell hypertrophy.
An early exposure to genistein was shown to increase
uterine tumorigenesis in adulthood through an epigenetic
pathway involving the decrease in the activity of the en-
hancer of zeste homologue 2 (EZH2) and levels of tri-
methylated lysine 27 on histone 3 (H3K27me3). Reduction
of H3K27me3 levels, a repressive mark for gene expression,
in developing uterus, reprogrammed estrogen-responsive
genes to become hyperresponsive to estrogen in adult uter-
us.24 It has been suggested that abnormalities inherent to the
eutopic endometrium, which are not found in the endome-
trium of women without endometriosis, may contribute to
ectopic growth outside the uterine cavity.25 One of these
abnormalities is the lower expression of Tetraspanin CD82,
a wide-spectrum tumor metastasis suppressor. Li et al.26
found that the mRNA and protein levels of CD82 in the
primary normal endometrial stromal cells (ESCs) from en-
dometrium without endometriosis are significantly higher
compared with the primary ESCs from eutopic endome-
trium and ectopic tissue. CD82 inhibits the invasiveness of
ESCs by downregulating the secretion of the chemokine
CCL2 and the expression of its receptor (CCR2). In the same
study, the authors showed that the combination of 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD, a highly carcinogenic
environmental chemical) with 17b-estradiol can promote
the invasion of ESCs by suppressing CD82 expression and
stimulating CCL2 secretion and CCR2 expression, and the
enhanced interaction of CCL2-CCR2 recruits more macro-
phages into the ectopic milieu in a paracrine manner, which
further downregulates CD82 expression in the ectopic
ESCs. These epigenetic and molecular events might be in-
volved in the development of endometriosis implants in soy-
supplemented animals.
Endometriosis was reported to exacerbate pelvic pain11 as
a result of an additional release of uterotonic agents by the
ectopic endometrium. In agreement with this report, our
results showed that the frequency of abdominal writhes
significantly increased and the writhing latency decreased in
the [ENDO+SF0%] group compared to sham-operated ani-
mals, both events characterizing abdominal pain.11 In ani-
mals supplemented with more than 10% of soy, the
frequency of abdominal writhes further increased and the
latency decreased in parallel, compared to soy-free-fed
 SOY INTAKE AND ENDOMETRIOSIS
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animals. This algetic effect of soy-enriched diets was as-
sociated with an increase in endometriotic implant volume
and supports the observations of Mvondo et al.,11 indicating
a positive correlation between the progress of endometriosis
and the severity of pelvic pain. These results therefore
suggest that the more the volume of endometriotic lesions
increases, the higher the intensity of pelvic pain is.
Regarding ovarian function, the literature reports that en-
dometriosis alters follicle maturation and ovulation processes,
resulting in an increased number of LUFs, which are thought
to account for the endometriosis-related subfertility.11,15,27 The
presence of more LUFs and reduced number of antral follicles
in the ovaries of animals with endometriosis was attributed to
the inhibitory effects of ectopic endometrium-released tissue
inhibitors of matrix metalloproteinases (TIMPs) on normal
follicular development and ovulation.15,27 Thus, the presence
of peritoneal endometriosis lesions makes the peritoneal en-
vironment in which the ovaries reside not suitable for follicular
growth and ovulation, probably because of its high content in
endometriotic TIMPs, resulting in reduced number of mature
(antral) follicles and increased number of LUFs in animals
with endometriosis, whatever their diet.
637
FIG. 6. Microphotographs ( · 400,
hematoxylin and eosin staining) of
uterine tissue. L = lumen, E = epithe-
lium, white arrows = mitosis, black
arrows = cellular necrosis.
Taken together, these results show that food supple-
mentation with roasted soybean flour induces immature
female rats to grow faster than animals receiving a soy-
free diet. However, in animals supplemented with more
than 10% of soy, the intensity of pelvic pain and the
volume of endometriotic lesions further increased as a
result of a sustained oxidative stress and cell hypertrophy
in these lesions. Results also showed that endometriosis
altered ovarian dynamic regardless of the amount of soy
ingested daily. Finally, although the supplementation of
rats with soy since the prepubertal stage improves growth
performance, its regular consumption may promote, in
adulthood, the survival and development of ectopic en-
dometrial cells and exacerbate in parallel endometriosis-
related pain, especially when soy content in food is more
than 10%.
ACKNOWLEDGMENT
The authors are thankful to the Research Unit of Animal
Physiology and Phytopharmacology of the University of
Dschang for material support.
 638 MVONDO ET AL.
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
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