Modern Rheumatology

ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20

Ovarian Reserve in Young Juvenile Idiopathic

Arthritis Patients

Gabriela R.V. Ferreira, Renato B. Tomioka, Nadia E. Aikawa, Elaine P.

Leon, Gustavo A.R. Maciel, Paulo C. Serafini, Edmund C. Baracat, Claudia
Goldenstein-Schainberg, Rosa M.R. Pereira, Eloisa Bonfá & Clovis A. Silva

To cite this article: Gabriela R.V. Ferreira, Renato B. Tomioka, Nadia E. Aikawa, Elaine P. Leon,
Gustavo A.R. Maciel, Paulo C. Serafini, Edmund C. Baracat, Claudia Goldenstein-Schainberg,
Rosa M.R. Pereira, Eloisa Bonfá & Clovis A. Silva (2018): Ovarian Reserve in Young Juvenile
Idiopathic Arthritis Patients, Modern Rheumatology, DOI: 10.1080/14397595.2018.1465646

To link to this article: https://doi.org/10.1080/14397595.2018.1465646

Accepted author version posted online: 13

Apr 2018.

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MORH-D-18-00031 Received: 23-Jan-2018; Accepted: 1-Apr-2018
Original Article

OVARIAN RESERVE IN YOUNG JUVENILE IDIOPATHIC ARTHRITIS PATIENTS

a b,c a,b b
Gabriela R.V. Ferreira, Renato B. Tomioka, Nadia E. Aikawa, Elaine P. Leon, Gustavo A.R.
c c c b
Maciel, Paulo C. Serafini, Edmund C. Baracat, Claudia Goldenstein-Schainberg, Rosa M.R.
b b a,b
Pereira, Eloisa Bonfá, Clovis A. Silva

t
ip
a
Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da

Universidade de São Paulo, Sao Paulo, BR

cr
b
Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da

Universidade de São Paulo, Sao Paulo, BR

c
us
Discipline of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade
an
de São Paulo, Sao Paulo, BR
M

CORRESPONDING AUTHOR: Clovis Artur Silva,

ed

Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo – SP, Brazil, 05403-000

Phone: 55-11-2661-8563, E-mail: clovis.silva@hc.fm.usp.br

pt
ce
Ac
Abstract

Objectives: Juvenile idiopathic arthritis (JIA) occurs during reproductive age, however, there are not

systematic data regarding ovarian function in this disease.

Methods: Twenty-eight post-pubertal JIA patients and age-matched 28 healthy controls were studied.

Complete ovarian function was assessed during the early follicular phase of the menstrual cycle

including anti-Müllerian hormone (AMH), estradiol, luteinizing hormone (LH), follicle stimulating

hormone (FSH) and antral follicle count (AFC) by ovarian ultrasound, and anti-corpus lutheum

antibodies (anti-CoL). Demographic data, menstrual abnormalities, disease parameters and treatment

were also evaluated.

t
Results: The mean current age (22.6±6.59 vs. 22.5±6.59 years, p=0.952) was similar in JIA patients

ip
and healthy controls with a higher median menarche age [13(8-16) vs. 12(8-14) years, p=0.029]. A

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lower median AMH levels [2.65(0.47-9.08) vs. 4.83(0.74-17.24)ng/mL,p=0.029] with a higher LH

[8.44±4.14 vs. 6.03±2.80IU/L, p=0.014] and estradiol levels [52.3(25.8-227.4) vs. 38.9(26.2-133.6)

us
pg/mL, p=0.008] were observed in JIA compared to control group. Anti-CoL and AFC were similar in

both groups (p>0.05). Further analysis of JIA patients revealed that current age, disease duration,
an
number of active/limited joints, ESR, CRP, patient/physician VAS, JADAS 71, DAS 28, CHAQ, HAQ,
M

patient/parents PedsQL, PF-SF 36, cumulative glucocorticoid and cumulative methotrexate doses

were not correlated with AMH, FSH, estradiol levels or AFC (p>0.05).
ed

Conclusions: The present study was the first to suggest diminished ovarian reserve, not associated

to hypothalamic pituitary gonadal axis, in JIA patients during reproductive age. The impact of this
pt

dysfunction in future fertility of these patients needs to be evaluated in prospective studies.

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Keywords: Juvenile idiopathic arthritis; ovarian reserve; anti-Müllerian hormone; fertility, anti-corpus

lutheum antibodies.
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Introduction

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized

by chronic arthritis of unknown etiology with onset before age of 16 years [1-3]. This chronic

inflammatory disease occurs mainly in females during the reproductive age, and ovarian reserve and

future fertility are relevant.

Evaluation of complete female gonadal function in juvenile rheumatic diseases including new

ovarian reserve markers such as anti-Müllerian hormone (AMH) levels and ovarian ultrasound [4-7],

and anti-corpus lutheum antibodies (anti-CoL) [7,8] was limited to childhood-onset systemic lupus

erythematosus (cSLE) and juvenile dermatomyositis (JDM) patients [8-10].

t
Thus, the objective of the present study was to assess ovarian reserve and anti-Col in JIA

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patients compared to healthy controls. The possible association between ovarian parameters and

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demographic data, gynecological history, clinical and laboratorial parameters of disease activity,

occurrence of anti-CoL and treatments were also evaluated.

Methods
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an
A cross-section study was conducted from September 2014 to June 2016 and all 110 female
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JIA patients, aged between 15 to 40 years, were invited. JIA patients fulfilled the International League

of Associations for Rheumatology (ILAR) classification criteria [11] and were followed at the Pediatric
ed

Rheumatology Unit or the Rheumatology Division of our tertiary university hospital.

The exclusion criteria were: contraindication or refusal to stop hormonal contraceptives for at
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least 6 months or until return of menstruation for 3 consecutive months or refusal to participate in this

study (n=64), amenorrhea (n=3), thyroid diseases (n=6), current gestation or lactation (n=3),
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polycystic ovarian syndrome (n=2), presence of another systemic autoimmune disease (n=2), obesity

in virgin patients, due to the difficulty performing the abdominal ultrasonography (n=1) and
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hypothalamic pituitary gonadal axis dysfunction (n=1). None of them had history of gynecological

surgery, pelvic irradiation due to neoplasia, use of gonadotrophin releasing hormone analogs, end-

stage renal disease or premature ovarian insufficiency [sustained amenorrhea before the age of 40

years, increased follicle-stimulating hormone (FSH) and decreased estrogen levels] [7]. Thus, after

the exclusion of 82 patients, 28 post-pubertal JIA patients were studied. The healthy age-matched

control group included 28 post-pubertal females adolescents or young adults, between 15 and 40
years of age, selected consecutively using the same exclusion criteria. The Local Ethics Committee

of our tertiary service approved the study and an informed consent was obtained from all participants

or their legal guardian.

Demographic data: The demographic data included: current age, ethnicity, socio economic class

[12], disease duration and body mass index (BMI). BMI was defined as weight in kilograms divided by
2
the square of height (m ).

Gynecological evaluation: Age at JIA menarche and controls were registered based on recollection.

t
Menstrual flow duration and cycle length were evaluated prospectively for at least 3 consecutive

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months. Normal cycle was defined as flow duration varying from 3 to 7 days and length from 25 to 35

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days [13-14]. Menstrual disturbances were based on alterations in one or more of these parameters

during evaluation. The mean cycle length and flow duration were also calculated. Amenorrhea was

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defined as the absence of menstrual periods for three consecutive cycles or a time period of more

than six months in a woman who was previously menstruating [13-14]. The presence of
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dysmenorrhea, menorrhagia, premenstrual syndrome, presence of cervical mucus and mid-menstrual
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cycle pain were also systematically evaluated.

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Ovarian reserve parameters: Complete ovarian function and other hormone profiles were assessed

in the first five days of menstrual cycle. The hormones were collected in fast morning, between 8 to 9
pt

AM. These hormones were evaluated blinded to the other parameters of ovarian function. Follicle-

stimulating hormone (FSH), luteinizing hormone (LH), estradiol, morning total testosterone,
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progesterone and prolactin were measured by electrochemiluminescence using a commercial kit

(Roche Diagnostics, Cobas 6000 analyzer series, Mannheim, Germany). Intra and inter-assay
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coefficients of variation were recommended by the manufacturer and limited to 2.2-5.1% and 1.9-

8.4%, respectively. AMH was measured by chemiluminescence assay (AMH, Beckman Coulter,

UniCel Dxi 800, Brea, CA) and intra and inter-assay coefficients of variation were limited to 9 and

7.8%, respectively.

Transvaginal ultrasound exams were performed by the same person (RBT), with a 4-10 MHz

endovaginal or a 2-8 MHz abdominal probe (Voluson S6, GE Healthcare Ultrasound). Antral follicle
count (AFC) and measurement of the ovarian volumes were performed through transvaginal

ultrasound (in sexually active patients and healthy controls) or abdominal (in virgin patients and

healthy controls) in the Discipline of Gynecology at the same university hospital. The AFC number was

counted during the early follicular phase, taking into account the number of follicles between 2 and 10

mm [15]. Ovaries were measured in 3 perpendicular planes and the ovarian volumes were calculated

using the ellipsoid formula (volume = D1 x D2 x D3 x 0.523), where D1, D2 and D3 are the maximum

diameters in the longitudinal, anteroposterior and transverse planes, respectively [16].

Diminished ovarian reserve (DOR) was characterized by AMH levels < 1.0 ng/mL or AFC < 7

[17].

t
ip
Detection of anti-corpus luteum antibody: Serum reactivity to the 67 kDa protein from corpus

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luteum was assessed by immunoblotting in duplicated samples from JIA patients and controls, as

previously described [18]. Crude tissue and cell extracts, obtained from bovine corpus luteum (100

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µg/well), were submitted to polyacrylamide gel electrophoresis under denaturating and reducing

conditions (β2-mercaptoethanol SDS-PAGE). Proteins were then electrophoretically transferred to

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nitrocellulose membrane. Membrane strips were further incubated with blocking buffer (5% skimmed
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milk in PBS) and immunoprobed by incubation with diluted serum samples 1/10. Reactivity was

tagged with anti-human IgG alkaline phosphatase conjugate and visualized using appropriate
ed

chromogenic substrates.
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Disease parameters, health-related quality of life and treatment:

Clinical assessment of JIA patients included: number of active and limited joints, patient and
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physician global assessment of arthritis activity measured in a 10cm horizontal visual analogy scale

(VAS). Disease activity was evaluated by the Juvenile Arthritis Disease Activity Score (JADAS71)
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(range: 0-101 points) for patients up to 18 years [19] and by the Disease Activity Score 28-Joint

Counts (DAS28) for patients over 18 years [20]. Validated Brazilian version of Childhood Health

Assessment Questionnaire (CHAQ) [21] was used for patients younger than 18 years of age and

Health Assessment Questionnaire (HAQ) for patients older than 18 years [22]. Health-related quality

of life was evaluated with Brazilian version of the Pediatric Quality of Life Inventory (PedsQL) for
patients up to 18 years [23] and short-form 36-item questionnaire (SF-36) for patients older than 18

years [24].

Use of non-steroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic

drugs - DMARDs (methotrexate, leflunomide, sulfasalazine and hydroxichloroquine), intravenous

cyclophosphamide and biological agents (etanercept, adalimumab, abatacept and tocilizumab) were

systematically assessed.

Statistical analysis: The results for the continuous variables were presented by median (minimum

and maximum value) or mean  standard deviation (SD), and for categorical variables presented as

t
frequency (percentage). The scores that had normal and abnormal distributions were compared by

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Student's t-test and Mann-Whitney test, respectively. The differences of categorical variables were

cr
calculated by Fisher's exact test or Pearson chi-square test, as appropriated. Pearson or Spearman

rank correlation coefficients were used for correlations between ovarian reserve parameters and

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demographic, disease and treatment variables. The adopted significance level in all analyses was set
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at 5%.
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Results

According to disease subtype, oligoarticular onset JIA was observed in 3/28 (11%) patients,
ed

polyarticular onset in 19/28 (68%), systemic onset in 5/28 (18%) and enthesitis-related arthritis in 1/28

(3%). DOR was similar in JIA patients and controls (11% vs. 11%, p=1.000).
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Table 1 shows demographic data and gynecological evaluation of JIA patients and healthy

controls. The mean current age (22.6 ± 6.59 vs. 22.5 ± 6.59 years, p=0.952) was similar in JIA
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patients and healthy controls with a higher median menarche age [13 (8-16) vs. 12 (8-14) years,

p=0.029]. No differences were observed of menstrual cycles parameters in both groups (p>0.05, Table
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1)

Table 2 illustrates hormone profile and other ovarian parameters and anti-CoL in JIA patients

and healthy controls. A lower median of AMH levels was observed in JIA patients compared to

controls [2.65 (0.47-9.08) vs. 4.83 (0.74-17.24) ng/mL, p=0.029]. A higher LH (8.44 ± 4.14 vs. 6.03 ±

2.80IU/L, p=0.014) and estradiol levels [52.3 (25.8-227.4) vs. 38.9 (26.2-133.6) pg/mL, p=0.008] were
observed in JIA versus controls. Anti-CoL (3% vs. 3%, p=1.0) and AFC [16.5 (6-57) vs. 20 (2-37),

p=0.935] were similar in both groups (p>0.05) (Table 2).

Regarding Pearson or Spearman’s rank correlations for JIA patients, current age, disease

duration, number of active/limited joints, ESR, CRP, patient/physician VAS, JADAS 71, DAS 28,

CHAQ, HAQ, patient/parents PedsQL, PF-SF 36, cumulative glucocorticoid and cumulative

methotrexate doses were not correlated with AMH, FSH, estradiol levels or AFC (p>0.05).

No differences were observed between JIA patients that received cumulative dose of

methotrexate  5 g (n=14) compared to those that received cumulative dose of methotrexate < 5 g

(n=12) in respect to ovarian parameters: FSH (6.89  1.21 vs. 7.20  2.30 IU/L, p=0.674), LH [6.9 (2.4-

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13.2) vs. 8.3 (4.1-23.2) IU/L, p=0.777], estradiol [54 (35.5-160.2) vs. 52.5 (25.8-227.4) pg/mL,

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p=0.857], AMH [2.24 (0.47-8.85) vs. 3.01 (1.03-9.08) ng/mL, p=0.554], right ovarian volume (4.39 

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1.66 vs. 6.17  2.88 cm , p=0.071), left ovarian volume [5.8 (2.2-27.1) vs. 5.4 (2.7-8) cm , p=0.662]
3 3

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and AFC [13.5 (8-40) vs. 17.5 (6-57), p=0.247]

No differences were evidenced between JIA patients that received biological agents (n=17)
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compared to those that did not receive these medications (n=11) regarding to all evaluated ovarian

parameters: FSH (6.91  1.89 vs. 7.04  1.78 IU/L, p=0.860), LH [7.8 (4.2-23-2) vs.7.9 (2.4-16) IU/L,
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p=0.778] estradiol [47.4 (25.8-227.4) vs. 57.1 (32.7-160.2) pg/mL, p=0.672], AMH levels [3.36 (0.64-

9.08) vs. 2.42 (0.47-6.47) ng/mL, p=0.323], right ovarian volume (5.47  2.31 vs. 5.07  2.72 cm ,
3
ed

3
p=0.677), left ovarian volume [6.3 (2.5-9.3) vs. 4.2 (2.2-27.1) cm , p=0.100] and AFC [16 (6-57) vs. 18

(8-34), p=0.906].
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No differences were evidenced between patients that JIA onset occurred before menarche
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(n=9) compared to those that menarche occurred after JIA onset (n=19) regarding the ovarian

parameters: FSH [6.2 (3.7-10.1) vs. 6.4 (4.7-12.2) IU/L, p=0.786), LH [6.5 (2.4-13.2) vs. 7.9 (4.2-23.2)
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IU/L, p=0.460], estradiol [41.5 (25.8-227.4) vs. 53.5 (37.6-160.2) pg/mL, p=0.089], AMH levels [2.65

(0.64-6.47) vs. 3.36 (0.47-9.08) ng/mL, p=0.824], right ovarian volume [4.4 (3.2-8.6) vs. 5.6 (1.5-12.8)
3 3
cm , p=0.325), left ovarian volume [5.05 (2.2-27.1) vs. 5.6 (2.2-8.9) cm , p= 0.948] and AFC [14 (9-33)

vs. 18 (6-57), p=0.475].

Discussion

The present study was the first to suggest diminished ovarian reserve, not associated to

hypothalamic pituitary gonadal axis, in JIA patients during reproductive age.

The main strength of this study was a complete ovarian reserve evaluation in post-pubertal

JIA patients and age-matched healthy controls at early follicular phase of menstrual cycle that

provided a more accurate estimation of follicle population and oocyte quality [25-31]. In addition, the

standardization of blood collection was important, since FSH production has circadian variation [7]. We

excluded patients and healthy controls with amenorrhea, and therefore none of the subjects had

premature ovarian insufficiency. The rigorous selection criteria of our JIA patients and controls lower

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than 40 years and without gynecologic diseases and hypothalamic-pituitary-ovary axis dysfunction

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were relevant since these abnormalities may influence ovarian reserve parameters [5-8,26-31].

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We also assessed hormone and anti-CoL profiles without the effect of any hormonal

contraceptives for at least three months to avoid possible bias, since AMH levels can be decreased in

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women using these birth control methods [32]. However, a limitation was small sample size due to

restricted inclusion and exclusion criteria.

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Dynamic test to assess ovarian reserve is not required for DOR diagnosis, since DOR is
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defined herein as decreased AFC or decreased AMH levels [17]. The significant lower values of AMH

in JIA patients suggest a reduction of ovarian follicle population, despite comparable values of AFC. In
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fact, the latter has low sensitivity and high specificity [33].

Although basal serum FSH and estradiol are used as ovarian reserve markers, it has
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demonstrated to have low accuracy to DOR diagnosis, since the reliability of both hormones is limited

due to high inter- and intra-menstrual cycle variability [33].

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Premature ovarian failure was previously described from 3.5% to 7.5% of JIA, mainly reported

in older patients (mean age 35 years) [34] and under chlorambucil for amyloidosis [35]. None of our
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JIA patients had this abnormality, because of their young age and also were never treated with this

alkylating agent. Moreover, amenorrhea was an exclusion criterion.

DOR in pediatric and adult autoimmune rheumatic diseases may occur due to aging, disease

activity, autoimmunity, and the use of immunosuppressive agents [4-6,36-41]. The similar age

between post-pubertal JIA patients and controls exclude this confounding variable and support the

notion of precociously reduced ovarian reserve in JIA patients. Disease activity does not seem to
affect reproductive health in our female JIA, contrasting to Behçet disease in which disease flare was

the most important contributing factor for reduced ovarian reserve [27].

DOR in JIA patients may be triggered by autoimmune mechanisms. Autoimmune oophoritis

may impact developing follicles, sparing primordial follicles during early phase due to CD4+ T cells

activation, inducing progressive decrease of ovarian function in mice. In humans, there are several

reported target antigens involved in autoimmune oophoritis, such as zona pellucida/oocyte, granulosa

cells, theca cells, steroidogenic enzymes and corpus luteum (anti-Col) [7]. The presence of anti-Col

was rarely observed in our JIA patients, contrasting with a prevalence of 16-22% in adult and cSLE

populations [8,18].

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Methotrexate seems to be not influence ovarian follicles population in JIA, contrasting with our

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previous study that demonstrated that a high cumulative methotrexate dose was a possible cause of

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ovarian dysfunction in adult c-SLE patients [8].

Biological agents do not seem to impair fertility in females [5,6], as also observed herein.

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Regarding immunosuppressive agents, intravenous cyclophosphamide was not a contributing factor to

diminished ovarian reserve in JIA patients, distinct for reports in SLE [8,10] and JDM patients [9]. This
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drug was used in solely in two patients with a total cumulative dose of less than 4 g and both had
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normal ovarian parameters (data not shown).

Delayed menarche was observed in JIA patients as also observed in cSLE [10,35-37] and
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JDM [9] patients.

In conclusion, the present study suggests that JIA patients have diminished ovarian reserve.
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The impact of this abnormality in future fertility of these patients needs to be evaluated in prospective

studies.
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Conflicts of interest: None

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Funding: Supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo

(FAPESP #2014/14806-0 to CAS; #2015/03756-4 to CAS), Conselho Nacional de Desenvolvimento

Científico e Tecnológico (CNPq 301805/2013-0 to RMRP, 305068/2014-8 to EB and 303422/2015-7

to CAS)), Federico Foundation (to RMRP, EB and CAS) and by Núcleo de Apoio à Pesquisa “Saúde

da Criança e do Adolescente” da USP (NAP-CriAd) to CAS.

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Ac
Table 1 - Demographic data and gynecological evaluation in juvenile idiopathic arthritis (JIA) patients
and healthy controls.
JIA Healthy controls
Variables p
(n=28) (n=28)
Demographic data
Current age, years 22.6  6.59 22.5  6.59 0.952
Caucasian 16 (57) 20 (71) 0.403
Socio-economic classes B or C 27 (96) 22 (79) 0.101
2
Body mass index, kg/m 22.1 (17.4-29.9) 21.8 (19.2-35.8) 0.991
Gynecological evaluation
Menstrual cycles
Age at menarche, years 13 (8-16) 12 (8-14) 0.029
Menstrual flow duration, days 5 (3-8) 5 (3-9) 0.451
Cycle length, days 28 (24-42) 28 (15-42) 0.787
Dysmenorrhea 16 (57) 11 (39.3) 0.285
Menorrhagia 3 (11) 4 (14) 1.000
Premenstrual syndrome 21 (75) 15 (54)

t
0.162

ip
Presence of cervical mucus 19 (68) 17 (61) 0.585
Mid-menstrual cycle pain 11 (39) 11 (39) 1.000
Values expressed as n (%), median (range) or mean ± standard deviation.

cr
us
an
Table 2 - Hormone profile and other ovarian parameters and anti-corpus luteum antibody in
juvenile idiopathic arthritis (JIA) patients and healthy controls.
JIA Healthy controls
Variables p
M

(n=28) (n=28)
Hormone profiles and ovarian
parameters
FSH, IU/L 6.4 (3.7-12.2) 6.3 (2.6-12.7) 0.317
ed

LH, IU/L 8.44  4.14 6.03  2.80 0.014

High values, > 12.6 IU/L 3 (11) 1 (3.6) 0.611
Estradiol, pg/mL 52.3 (25.8-227.4) 38.9 (26.2-133.6) 0.008
pt

High values, > 233 pg/mL 0 (0) 0 (0) 1.000

AMH, ng/mL 2.65 (0.47-9.08) 4.83 (0.74-17.24) 0.029
Reduced values, < 1.0 ng/mL 2 (7) 2 (7) 1.000
ce

3
Right ovarian volume, cm 4.9 (1.5-12.8) 6.1 (2-16.1) 0.099
3
Left ovarian volume, cm 5.1 (2.2-27.1) 5.6 (2.1-15.6) 0.966
AFC 16.5 (6-57) 20 (2-37) 0.222
Ac

Reduced values, < 7 1 (3) 1 (3) 1.000

Progesterone, ng/mL 0.4 (0.2-1.2) 0.4 (0-1.5) 0.935
Morning total testosterone, ng/dL 26 (11-90) 19.5 (11-68) 0.317
Prolactin, ng/mL 13.3 (5.6-29) 11 (4.4-31) 0.108
Diminished ovarian reserve 3 (11) 3 (11) 1.000
Anti-corpus luteum antibody 1 (3) 1 (3) 1.000
Values expressed as n (%), median (range) or mean ± standard deviation, FSH - follicle stimulating
hormone, LH - luteinizing hormone, AMH - anti-Müllerian hormone, AFC - antral follicle count.