Nickel Allergy Is a Risk Factor for Endometriosis: An 11-Year Population-Based Nested Case-Control Study

Abstract

Background:
A cross-sectional study has reported that nickel allergy is associated with endometriosis. However, causal studies of this association are limited.

Objective:
The objective of this study was to compare the prevalence of nickel allergy in women with and without endometriosis.

Methods:
We used a National Health Insurance Service (NHIS) sample cohort dataset that included approximately 1 million individuals from South Korea; the data were obtained between January 01, 2002, and December 31, 2013. We selected the endometriosis group according to diagnosis code (N80.X), surgery codes, and drug codes during the years 2009~2013. The controls were randomly matched to the endometriosis patients at a ratio of 4:1 by age and socioeconomic status. Patients with nickel allergy were defined in the cohort dataset as those with a simultaneous diagnosis code (L23.0) and patch test code during 2002~2008.

Results:
In total, 4,985 women were selected from the NHIS cohort database and divided into an endometriosis group (997 women) and a control group (3,988 women). The number of patients with nickel allergy in the endometriosis group was eight (0.8%), and that in the control group was thirteen (0.3%). After adjustment for age and socioeconomic status, the rate of nickel allergy in was higher in the endometriosis group than in the control group [odds ratio: 2.474; 95% confidence interval: 1.023~5.988; p = 0.044].

Conclusions:
We found that nickel allergy is a risk factor for endometriosis.

Full text

RESEARCH ARTICLE
Nickel Allergy Is a Risk Factor for
Endometriosis: An 11-Year Population-Based
Nested Case-Control Study
Jin-Sung Yuk
1,2
, Jong Seung Shin
3
, Ji-Yeon Shin
4
, Eunsuk Oh
5
, Hyunmee Kim
6
, Won
I. Park
1
*
1Department of Obstetrics and Gynecology, School of Medicine, Eulji University, Daejeon, South Korea,
2Department of Obstetrics and Gynecology, MizMedi Hospital, Seoul, South Korea, 3Department of
Obstetrics and Gynecology, Hyundai UVIS hospital, Incheon, South Korea, 4Department of Preventive
Medicine, School of Medicine, Eulji University, Daejeon, South Korea, 5Department of Internal Medicine,
MizMedi Hospital, Seoul, South Korea, 6Department of Family Medicine, MizMedi Hospital, Seoul, South
Korea
*pwi3110@eulji.ac.kr
Abstract
Background
A cross-sectional study has reported that nickel allergy is associated with endometriosis.
However, causal studies of this association are limited.
Objective
The objective of this study was to compare the prevalence of nickel allergy in women with
and without endometriosis.
Methods
We used a National Health Insurance Service (NHIS) sample cohort dataset that included
approximately 1 million individuals from South Korea; the data were obtained between Jan-
uary 01, 2002, and December 31, 2013. We selected the endometriosis group according to
diagnosis code (N80.X), surgery codes, and drug codes during the years 2009~2013. The
controls were randomly matched to the endometriosis patients at a ratio of 4:1 by age and
socioeconomic status. Patients with nickel allergy were defined in the cohort dataset as
those with a simultaneous diagnosis code (L23.0) and patch test code during 2002~2008.
Results
In total, 4,985 women were selected from the NHIS cohort database and divided into an
endometriosis group (997 women) and a control group (3,988 women). The number of
patients with nickel allergy in the endometriosis group was eight (0.8%), and that in the con-
trol group was thirteen (0.3%). After adjustment for age and socioeconomic status, the rate
of nickel allergy in was higher in the endometriosis group than in the control group [odds
ratio: 2.474; 95% confidence interval: 1.023~5.988; p = 0.044].
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 1/8
OPEN ACCESS
Citation: Yuk J-S, Shin JS, Shin J-Y, Oh E, Kim H,
Park WI (2015) Nickel Allergy Is a Risk Factor for
Endometriosis: An 11-Year Population-Based Nested
Case-Control Study. PLoS ONE 10(10): e0139388.
doi:10.1371/journal.pone.0139388
Editor: Esaki Muthu Shankar, University of Malaya,
MALAYSIA
Received: June 27, 2015
Accepted: September 11, 2015
Published: October 6, 2015
Copyright: © 2015 Yuk et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data were
obtained from the National Health Insurance Sharing
Service (NHISS) and are available upon request
through http://nhiss.nhis.or.kr/bd/ab/bdaba021eng.do.
Funding: The authors have no support or funding to
report.
Competing Interests: The authors have declared
that no competing interests exist.

Conclusions
We found that nickel allergy is a risk factor for endometriosis.
Introduction
Endometriosis is an estrogen-dependent disease that causes pelvic pain and subfertility in
6–10% of women [1]. Although debate continues regarding the cause of endometriosis, the
central theory involves the retrograde flow of endometrial cells into the pelvic cavity during
menstruation [1,2]. However, the main weakness of this theory is that only 6–10% of all
women have retrograde menstruation [1]; thus, some complementary theories are needed. One
hypothesis is that environmental substances such as dioxin, polychlorinated biphenyls and
organochlorine pesticides may cause endometriosis [3,4]. Another hypothesis is that changes
in the immune response might affect the survival of endometrial cells external to the endome-
trium [5,6].
Recently, using national claims data in South Korea, Yuk et al. demonstrated a high rate of
nickel allergy in women with endometriosis [7]. Because nickel allergy involves features of
environmental exposure and the immune response, there may be a relationship between nickel
allergy and the pathogenesis of endometriosis [8]. However, the study of Yuk et al. was not a
causal study but rather a correlational study. Thus, it is unclear which disease precedes the
other.
The aim of this nested case-control study was to evaluate the prevalence of nickel allergy in
women with and without endometriosis using national claims cohort data collected from 2002
to 2013. To the best of our knowledge, this is the first nested case-control study to assess the
causal relationship between nickel allergy and endometriosis.
Materials and Methods
Sample
We used a sample cohort dataset provided by the National Health Insurance Service (NHIS)
[9]. These data corresponded to approximately 1 million individuals selected randomly from
almost all South Koreans, totaling 45 million people, with national claims data for the period
from January 1, 2002, to December 31, 2013. The included variables were gender, 5-year age
group, socioeconomic status (with subjects divided into 10 categories based on income), diag-
nosis code, surgery code, drug prescription data (drug name, dosage, and date of prescription)
and billing code.
Selection of subjects
We used the International Classification of Diseases (ICD) 10
th
edition to extract the endome-
triosis group and the control group. We selected the endometriosis group as follows. We
excluded patients with any endometriosis diagnosis code (N80.X) prior to 2009 from the endo-
metriosis group. We selected patients with an endometriosis diagnosis code (N80.X) assigned
between 2009 and 2013 from the NHIS sample cohort data collected during 2002–2013 (Fig 1).
Among these endometriosis patients, we selected patients who simultaneously had an endome-
triosis diagnosis code (N80.X) and one or more of the following surgery codes [R4122 (myo-
mectomy), R4160 (pelvic adhesiolysis), R4165 (fulguration), R4166 (foreign body removal),
R4170 (metroplasty of uterine anomaly), R4181 (Kustner operation), R4182 (manual
Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 2/8

Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 3/8

reduction), R4183 (total hysterectomy), R4331 (unilateral adnexectomy), R4332 (bilateral
adnexectomy), R4341 (ligation of fallopian tubes), R4342 (surgical fulguration of oviducts),
R4345 (laparotomy), R4421 (extirpation of benign adnexal tumor), R4430 (ovarian wedge
resection), R4435 (incision and drainage of ovarian cyst)]; patients with a simultaneous endo-
metriosis diagnosis code (N80.X) and gonadotropin-releasing hormone (GnRH) agonist code
[182602BIJ (leuprolide acetate), 182604BIJ (leuprolide acetate), 244902BIJ (triptorelin acetate),
167202BIJ (goserelin acetate), 167201BIJ (goserelin acetate), 198501CSI (nafarelin)]; and
patients with a simultaneous endometriosis diagnosis code (N80.X) and danazol code
(140301ACH, 140302ACH) to increase diagnostic accuracy. Among patients without any
endometriosis diagnosis code (N80.X) during 2002~2013, the controls were randomly matched
to the endometriosis patients at a ratio of 4:1 by 5-year age group and socioeconomic status
(Fig 1). Patients with nickel allergy were identified as those who simultaneously had a nickel
allergy diagnosis code (L23.0) and a test code [patch test (E7130), skin prick test (E7151,
EY853), intradermal test (E7152, EY854)] among the cohort dataset during 2002–2008.
Statistics
Data management and analysis were performed using the R statistical software (version 3.0.3;
Vienna, Austria). Significance was considered for p-values under 0.05. All of the statistical
analyses were performed using two-tailed tests. The chi-squared test or Fisher’s exact test was
applied to compare categorical differences between two groups. After adjustments for age,
socioeconomic status and sampling year, conditional logistic multivariate analysis was per-
formed to determine the effects of nickel allergy on endometriosis.
Ethics statement
For information protection, all of the patients received an anonymous identification code in
the sample data provided by the NHIS. The authors could not identify any patients in the sam-
ple data. Thus, we did not require the approval of the Institutional Review Board, in accordance
with the guidelines of the Institutional Review Board of MizMedi Hospital.
Results
A total of 4,985 women were selected from the NHIS cohort database, which included approxi-
mately 1 million individuals from 2002 to 2013. Among the 4,985 women, the endometriosis
group included 997 women. The control group included 3,988 women who were matched to
the endometriosis patients according to 5-year age group and socioeconomic status at a ratio of
4:1 (Fig 1 and Table 1). The mean age in both groups was 42.6±9.3 years in 2013. The number
of patients with nickel allergy in the endometriosis group was eight (0.8%), and the number of
patients with nickel allergy in the control group was thirteen (0.3%). After adjusting for 5-year
age group and socioeconomic status, the prevalence of nickel allergy was higher in the endome-
triosis group than in the control group [odds ratio (OR): 2.474; 95% confidence interval (CI):
1.023–5.988; p = 0.044] (Table 2).
Fig 1. Flow chart representing the selection procedure based on the NHIS cohort data set from 2002–2013.
a
Surgery codes: R4122, R4160, R4165,
R4166, R4170, R4181, R4182, R4183, R4331, R4332, R4341, R4342, R4345, R4421, R4430, and R4435.
b
Gonadotropin-releasing hormone agonist
codes and danazol codes: 182602BIJ, 182604BIJ, 244902BIJ, 167202BIJ, 167201BIJ, 198501CSI, 140301ACH, and 140302ACH. Abbreviations: EMS,
Endometriosis; NHIS, National Health Insurance Service; GnRH, Gonadotropin-releasing hormone.
doi:10.1371/journal.pone.0139388.g001
Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 4/8

Discussion
Nickel is a silvery-white metal that is mainly used as an alloy with iron, copper, chromium, and
zinc, and it is used for plating, coins, batteries, jewelry, buttons, eyeglasses, zippers, valves, heat
exchangers, and promoters [10]. Nickel allergy has a prevalence that ranges from 10–23%
among women [11,12], and it is one of the most common forms of allergic contact dermatitis,
which results in itching, redness, rash, dryness, swelling and blisters [13].
Our case-control study suggests that nickel allergy is a risk factor for endometriosis. To
date, there has been little quantitative analysis of the relationship between nickel allergy and
endometriosis. Recently, one study showed that nickel concentrations in the blood of patients
with endometriosis were higher than those in a control group [14]. More recently, Yuk et al.
reported a positive relationship between nickel allergy and endometriosis using a cross-sec-
tional population-based study [7]. However, no previous study has evaluated the causal link
between nickel allergy and endometriosis.
It is not yet clear why nickel allergy is a risk factor for endometriosis, although the studies
discussed below could provide clues on this topic. The occurrence of nickel allergy increases
Table 1. Characteristics of patients in the endometriosis group and the control group, 2002–2013.
EMS group Control group Total p-value
Number of patients 997 3,988 4,985
2009
a
183
2010
a
198
2011
a
198
2012
a
201
2013
a
217
Mean age group
b
8.5±1.8 8.5±1.9 8.5±1.8 1
Mean age (years)
c
42.6±9.2 42.6±9.3 42.6±9.3
Mean group socioeconomic status
d
6.0±2.9 6.0±2.9 6.0±2.9 1
Nickel allergy 0.052
e
Present 8 (0.8%) 13 (0.3%) 21
Not present 989 (99.2%) 3975 (99.7%) 4964
a
First diagnosis of EMS was made in the year noted.
b
Mean age groups per 5 years in 2013. 1; 0–4 years, 2; 5–9 years,......., 17; 80–84 years, 18; 85 years+.
c
The mean age was calculated from the mean age groups per 5 years.
d
Mean socioeconomic status groups in 2013. 1; upper 0–9%, 2; upper 10–14%,......., 9; upper 90–94%, 10; upper 95%+.
e
Fisher’s exact test
Data are presented as numbers or means ±standard deviations
doi:10.1371/journal.pone.0139388.t001
Table 2. Multivariate logistic regression analysis of endometriosis and nickel allergy.
Adjustment Crude OR Adjusted OR
a
OR (95% CI) p-value OR (95% CI) p-value
Age group per 5 years 1.001 (0.963~1.038) 1 1.001 (0.964~1.039) 0.977
Socioeconomic status group (decile) 1.000 (0.976~1.024) 1 1.000 (0.976~1.024) 0.977
Nickel allergy 2.473 (1.022~5.984) 0.045 2.474 (1.023~5.988) 0.044
a
Covariates: Age group per 5 years, socioeconomic status group (decile), nickel allergy.
CI, Confidence interval; OR, Odds ratio
doi:10.1371/journal.pone.0139388.t002
Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 5/8

with exposure to nickel. As an example, one study has reported that women, who are frequently
exposed to nickel accessories, show a higher prevalence of nickel allergy than men, who are not
[8]. In addition, there is a higher prevalence of nickel allergy among hairdressers, who fre-
quently use nickel alloy scissors, and retail clerks, who handle coins more frequently than the
general population [8]. Because frequent exposure to nickel occurs throughout daily life, nickel
allergy has been associated with high nickel levels in the blood [15,16]. Thus, a high blood con-
centration of nickel in patients with nickel allergy might cause endometriosis.
If this relationship is true, what characteristics of nickel might cause endometriosis?
Although we do not know the exact reason, the estrogenic characteristics of nickel might affect
endometriosis [17,18]. Specifically, nickel can bind the metal-binding sites on the estrogen
receptor (ER) in vitro [19], and nickel has also been shown to stimulate ERαexpression and
activity in breast cancer cells [20]. Furthermore, nickel concentrations in blood, urine, hair,
and breast tumor tissues have been positively correlated with breast tumors [18]. Several such
lines of evidence suggest that nickel has estrogenic characteristics. Similarly, certain chemicals
have estrogen-like characteristics [21,22], and estrogens have an important effect on endome-
triosis [1]. In conclusion, nickel allergy is associated with high nickel blood levels, and these
high nickel levels might affect the development of endometriosis due to the estrogenic effects
of nickel.
As discussed earlier, endometriosis and nickel allergy may share a common pathogenesis
[8]. The underlying mechanism of nickel allergy is delayed cell-mediated hypersensitivity [23].
Similarly, endometriosis is related to an increased T-helper 1 response, which plays a key role
in cell-mediated hypersensitivity [24].In addition, certain autoimmune diseases, such as auto-
immune thyroiditis, involve increased lymphocyte reactivity to nickel [25].Nickel allergy pre-
dominantly affects women [11]. These findings indicate that nickel may exhibit autoimmune
characteristics. Given the autoimmune characteristics of endometriosis, endometriosis and
nickel allergy may share common features [26]. However, the some characteristics of the
immune response in each disease are different; nickel allergy is an immunologic cell-mediated
response involving a hapten (a low-molecular-weight compound) [27], whereas endometriosis
has not been associated with any trigger chemicals, such as haptens, to date. Additionally,
endometriosis is not related to other allergic diseases such as allergic rhinitis, atopic dermatitis
or even other forms of contact dermatitis, with the exception of nickel allergy, according to a
cross-sectional population-based study [7]. It thus remains unclear whether immune dysregu-
lation caused by nickel exposure is a causal mechanism in the development of endometriosis.
Our results should be interpreted with caution. Because the prevalence of women in whom
nickel allergy preceded endometriosis was only 0.8%, the influence of nickel allergy in the path-
ogenesis of endometriosis may be of low clinical importance. However, most cases of nickel
allergy are diagnosed clinically based on history and physical examination findings [28]. In
contrast, in our study, we restricted our cohort of patients with nickel allergy to women who
had undergone patch testing to increase the accuracy of the diagnosis. Therefore, the number
of patients with nickel allergy might be underestimated in our study. In support of this possibil-
ity, the prevalence of nickel allergy was only 0.3% in the control group. Considering that the
prevalence of nickel allergy ranges from 10–23% in the general population, the true prevalence
of nickel allergy in our study might be much higher than 0.3% [11,12]. Therefore, although it is
impossible to assert that nickel allergy affects all patients with endometriosis, nickel allergy
might be one of several causes influencing the development of endometriosis.
This study also had several limitations. First, there was a lack of patient data regarding the
histological findings and staging of endometriosis. To complement this point, only endometri-
osis patients who had undergone surgery or received a GnRH agonist or a danazol injection
were included in our study. Despite these efforts, there may be some limitation to the analysis
Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 6/8

of endometriosis, especially regarding stage. Second, there is a possibility that patients were
miscoded with respect to their diagnosis, examination, surgery or administered drugs. How-
ever, because the possibility of miscoding was similar in the endometriosis group and the con-
trol group, the influence of this possibility may be limited. Third, our data did not include the
stage of endometriosis, obstetric history or occupation. Thus, we could not adjust for those var-
iables in our logistic regression analysis.
In conclusion, we found that nickel allergy is a risk factor for endometriosis. Further study
with greater focus on the irritant features or immune response to nickel is suggested.
Author Contributions
Conceived and designed the experiments: JSY JSS. Analyzed the data: JYS. Wrote the paper:
EO HK WIP.
References
1. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012; 98:
511–519. doi: 10.1016/j.fertnstert.2012.06.029 PMID: 22819144
2. Sampson J. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the
peritoneal cavity. Am J Obstet Gynecol. 1927; 14: 93–94.
3. Bruner-Tran KL, Yeaman GR, Crispens MA, Igarashi TM, Osteen KG. Dioxin may promote inflamma-
tion-related development of endometriosis. Fertil Steril. 2008; 89: 1287–1298. doi: 10.1016/j.fertnstert.
2008.02.102 PMID: 18394613
4. Upson K, De Roos AJ, Thompson ML, Sathyanarayana S, Scholes D, Barr DB, et al. Organochlorine
pesticides and risk of endometriosis: findings from a population-based case-control study. Environ
Health Perspect. 2013; 121: 1319–1324. doi: 10.1289/ehp.1306648 PMID: 24192044
5. Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dys-
function or autoimmune disease? Trends Mol Med. 2003; 9: 223–228. PMID: 12763528
6. Rier SE. Environmental immune disruption: a comorbidity factor for reproduction? Fertil Steril. 2008;
89: e103–108. doi: 10.1016/j.fertnstert.2007.12.040 PMID: 18308048
7. Yuk J-S, Kim YJ, Yi K-W, Tak K, Hur J-Y, Shin J-H. High rate of nickel allergy in women with endometri-
osis: A 3-year population-based study. J Obstet Gynaecol Res. 2015
8. Thyssen JP, Milting K, BregnhøjA,Søsted H, Duus Johansen J, Menné T. Nickel allergy in patch-
tested female hairdressers and assessment of nickel release from hairdressers’scissors and crochet
hooks. Contact Dermatitis. 2009; 61: 281–286. doi: 10.1111/j.1600-0536.2009.01624.x PMID:
19878243
9. National Health Insurance Data Sharing Service (NHISS) [Internet]. [cited 17 Apr 2015]. Available:
http://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do;jsessionid = thbGlRHMum10cMHqTOBhKUWdA1k0vr
3zoarVeFFl5wtug7WK66Gz267GcW0no7GC.primrose2_servlet_engine1
10. ATSDR—Toxicological Profile: Nickel. In: ATSDR [Internet]. 2015 [cited 1 Jun 2015]. Available: http://
www.atsdr.cdc.gov/toxprofiles/tp.asp?id=245&tid=44
11. Cheng T-Y, Tseng Y-H, Sun C-C, Chu C-Y. Contact sensitization to metals in Taiwan. Contact Dermati-
tis. 2008; 59: 353–360. doi: 10.1111/j.1600-0536.2008.01468.x PMID: 19076886
12. Thyssen JP, Johansen JD, Carlsen BC, Menné T. Prevalence of nickel and cobalt allergy among
female patients with dermatitis before and after Danish government regulation: a 23-year retrospective
study. J Am Acad Dermatol. 2009; 61: 799–805. doi: 10.1016/j.jaad.2009.03.030 PMID: 19632002
13. Darlenski R, Kazandjieva J, Pramatarov K. The many faces of nickel allergy. Int J Dermatol. 2012; 51:
523–530. doi: 10.1111/j.1365-4632.2011.05233.x PMID: 22515577
14. Silva N, Senanayake H, Waduge V. Elevated levels of whole blood nickel in a group of Sri Lankan
women with endometriosis: a case control study. BMC Res Notes. 2013; 6: 13. doi: 10.1186/1756-
0500-6-13 PMID: 23317102
15. Gammelgaard B, Veien NK. Nickel in nails, hair and plasma from nickel-hypersensitive women. Acta
Derm Venereol. 1990; 70: 417–420. PMID: 1980976
16. Boscolo P, Di Gioacchino M, Conti P, Barbacane RC, Andreassi M, Di Giacomo F, et al. Expression of
lymphocyte subpopulations, cytokine serum levels and blood and urine trace elements in nickel sensi-
tised women. Life Sci. 1998; 63: 1417–1422. PMID: 9952287
Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 7/8

17. Darbre PD. Metalloestrogens: an emerging class of inorganic xenoestrogens with potential to add to
the oestrogenic burden of the human breast. J Appl Toxicol JAT. 2006; 26: 191–197. doi: 10.1002/jat.
1135 PMID: 16489580
18. Aquino NB, Sevigny MB, Sabangan J, Louie MC. The role of cadmium and nickel in estrogen receptor
signaling and breast cancer: metalloestrogens or not? J Environ Sci Health Part C Environ Carcinog
Ecotoxicol Rev. 2012; 30: 189–224. doi: 10.1080/10590501.2012.705159
19. Medici N, Minucci S, Nigro V, Abbondanza C, Armetta I, Molinari AM, et al. Metal binding sites of the
estradiol receptor from calf uterus and their possible role in the regulation of receptor function. Biochem-
istry (Mosc). 1989; 28: 212–219.
20. Martin MB, Reiter R, Pham T, Avellanet YR, Camara J, Lahm M, et al. Estrogen-like activity of metals in
MCF–7 breast cancer cells. Endocrinology. 2003; 144: 2425–2436. PMID: 12746304
21. Defrère S, Lousse JC, González-Ramos R, Colette S, Donnez J, Van Langendonckt A. Potential
involvement of iron in the pathogenesis of peritoneal endometriosis. Mol Hum Reprod. 2008; 14: 377–
385. doi: 10.1093/molehr/gan033 PMID: 18508952
22. Heilier JF, Donnez J, Verougstraete V, Donnez O, Grandjean F, Haufroid V, et al. Cadmium, lead and
endometriosis. Int Arch Occup Environ Health. 2006; 80: 149–153. doi: 10.1007/s00420-006-0114-7
PMID: 16688463
23. Becker D. Allergic contact dermatitis. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG. 2013; 11: 607–
619; quiz 620–621. doi: 10.1111/ddg.12143
24. Podgaec S, Dias Junior JA, Chapron C, Oliveira RM de, Baracat EC, Abrão MS. Th1 and Th2 ummune
responses related to pelvic endometriosis. Rev Assoc Médica Bras 1992. 2010; 56: 92–98.
25. Hybenova M, Hrda P, Procházková J, Stejskal V, Sterzl I. The role of environmental factors in autoim-
mune thyroiditis. Neuro Endocrinol Lett. 2010; 31: 283–289. PMID: 20588228
26. Sundqvist J, Falconer H, Seddighzadeh M, Vodolazkaia A, Fassbender A, Kyama C, et al. Endometri-
osis and autoimmune disease: association of susceptibility to moderate/severe endometriosis with
CCL21 and HLA-DRB1. Fertil Steril. 2011; 95: 437–440. doi: 10.1016/j.fertnstert.2010.07.1060 PMID:
20797713
27. Peiser M, Tralau T, Heidler J, Api AM, Arts JHE, Basketter DA, et al. Allergic contact dermatitis: epide-
miology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assem-
bled at an international workshop at BfR, Germany. Cell Mol Life Sci CMLS. 2012; 69: 763–781. doi:
10.1007/s00018-011-0846-8 PMID: 21997384
28. Usatine RP, Riojas M. Diagnosis and management of contact dermatitis. Am Fam Physician. 2010; 82:
249–255. PMID: 20672788
Nickel Allergy Is a Risk Factor for Endometriosis
PLOS ONE | DOI:10.1371/journal.pone.0139388 October 6, 2015 8/8