Introduction
Autoimmune diseases are a wide range of disorders in which the immune system attacks self-antigens resulting in damage or dysfunction of the tissues. During puberty, autoimmune rheumatic diseases (ARD) are more common in females than in males like juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE), and juvenile dermatomyositis (JDM), which may derail the normal stages of puberty or menstruation [
1].
Puberty is the acquisition of secondary sex characteristics that associated with the growth spurt, resulting in the accomplishment of reproductive function and final height [
2]. The presence of one or more of the following clinical and laboratory parameters defined normal gonadal function: normal menstrual cycles with or without dysmenorrhea, elevated cervical mucus length, normal levels of plasma follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone, prolactin, and testosterone. In addition to the normal urinary hormonal cytology or serial pelvic ultrasound (US) compatible with ovulatory pattern [
3].
Disorders of puberty can profoundly impact the physical and psychosocial well-being. Precocious puberty is the pubertal onset before eight years of age in girls, while delayed puberty is defined as the outset of pubertal changes was delayed more than 13 years in girls, or age of menarche > 16 years [
4].
The gonadal function alternation may be mediated by several factors that related to the adolescence and ARD, such as physiologic anovulation of adolescence, dysfunction of the hypothalamic–pituitary–ovarian axis, thyroid disorders, and the immunosuppressant agents used, particularly cyclophosphamide and corticosteroids [
5‐
7].
Health care providers who counselling adolescents with juvenile ARDs need to take in consideration of these problems to minimize the negative impact of ARDs and their medications. Patients and families will benefit from the increased awareness of the relationship between ARDs and ovarian dysfunction, menstrual abnormalities, or puberty disorders.
Studies that addressed the impact of ARDs on ovarian function or puberty-related outcome are scare. This study aimed to shed light on the different menstrual and pubertal abnormalities observed in young females with systemic ARDs, and its relation to the various disease parameters.
Patients and method
This cross-sectional study was conducted on a group of adolescent girls with ARDs attending to the Paediatric Rheumatology Clinic, Mansoura University Children’s Hospital. The study was conducted from October 2021 till December 2022 and all eligible cases were collected along this duration according to the inclusion criteria.
Inclusion criteria
Adolescent girls aged 13–18 years with the following ARDs:
a)
JIA cases who are classified based on the International League of Associations for Rheumatology (ILAR) criteria [
8].
b)
JSLE patients who are classified according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria for Systemic Lupus Erythematosus [
9].
c)
JDM girls who are classified on the basis of the EULAR/ACR classification criteria for juvenile idiopathic inflammatory myopathies and their major subgroups [
10].
Exclusion criteria
1.
Patients with other chronic diseases (endocrinal, reproductive, neurological, or cardiac), which may affect the pubertal maturity or regular menstruation.
2.
Females using hormonal contraceptive agents.
3.
Patients/ parents refuse to share in this special research.
Work plan
Data were collected from our patients’ files and interpreted with respect to the demographic, clinical, disease assessment parameters, medications used, and the hormonal profile as follows:
1.
Disease assessment indices at the time of enrollment including: disease activity by juvenile arthritis disease activity score-10 (JADAS-10) [
11], disease damage by juvenile arthritis damage (JAD) index [
12] in case of JIA, while in JSLE cases; the disease activity and cumulative damage were measured using the SLE Disease Activity Index 2000 (SLEDAI-2 K) [
13] and the Systemic Lupus International Collaborating Clinics/ACR (SLICC/ACR) Damage Index, respectively [
14]. In cases with JDM, Myositis disease activity assessment tool (MDAAT) was used [
15].
2.
Laboratory investigations: Complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function tests, serum creatinine, complement, urine analysis, muscle enzymes, and autoimmune profile (anti-nuclear antibody (ANA), rheumatoid factor (RF), Anti-dsDNA) as routine laboratory tests in caring for cases with ARDs. The determination of serum hormonal levels was at the follicular phase (between day 2 and day 7 of the menstrual cycle or randomly for girls with amenorrhoea), including E2 (normal range: 22–215 pg/mL), LH (1.1–11.6 mIU/L), FSH (3–14.4 mIU/L), and prolactin (1.9–25 ng/mL) [
16].
The following aspects of puberty were assessed: the age at puberty onset, age at menarche, menstrual abnormalities, and the length of menstrual flow. Each patient was examined by a gynaecologist for secondary sexual characteristics according to the Marshall and Tanner’s pattern of pubertal changes [
17] then they were specified according to the breast maturity into B1–B5 and pubic hair maturity into PH1– PH5. Pubertal onset is defined as the onset of B2/PH2, meanwhile delayed puberty is identified as the age at B2/PH2 > 13 years or onset of menarche > 16 years [
18].
The normal cycle was identified as having a cycle length varying from 28 to 35 days, with 3–7 days of blood flow. Menstrual irregularities were based on alterations in one or more of these parameters. While, amenorrhoea and sustained amenorrhoea is defined as the cessation of menstruation for more than 4 months after menarche and persisting for more than 12 months, respectively [
3,
16].
US assessment was performed using a 7.5 MHz scan at the follicular phase (2nd or 3rd day of menstruation). The evaluated US parameters were the diameter of endometrium (normal 6–10 mm) and ovarian volumes (normal 8–10cm3) [
3].
Statistical analysis
Data were analysed using the IBM-Statistical Package of Social Science (SPSS) program for Windows (version 22). The normality of data was first tested. Qualitative data were described using numbers and percentages. Continuous variables were presented as mean ± standard deviation (SD) for normally distributed data and median (min-max) for non-normal data. The comparison between the three ARDs was performed with the Kruskal-Wallis test while the Mann Whitney test was used between those with menstrual abnormalities versus those with regular cycle within each ARD.
The comparison between the categorical variables was tested using the Chi-square test while the Fischer exact test was used when the expected cell count less than 5. The Spearmen correlation was utilized to detect the association between the age of menarche, disease duration, activity, and the cumulative doses of steroid in girls with ARDs. The logistic regression model was performed to predict the most significant determinants for menstrual abnormalities. The odds ratio (OR) was calculated with 95% confidence intervals. The results were considered significant when p ≤ 0.05.
Discussion
There are few descriptions of menstrual abnormalities in adolescents with ARDs in the medical literature. In our study, we performed a comprehensive assessment of the impact of the three major ARDs on the ovarian function and puberty. Our analysis revealed that JSLE cases had a higher rate of menstrual abnormalities more than JIA or JDM girls. The damage index was statistically higher in JSLE with abnormal menstrual cycles, similarly were the cumulative steroid dose. However, no difference was observed between JIA or JDM subgroups. The most significant predictor for menstrual abnormalities in JSLE was the SLICC/ACR damage index as inferred from the regression analysis.
Ten patients with JSLE (47.6%) had menstrual abnormalities, whereas only four JIA and 1 JDM girls had these alterations without significant difference between the three groups. Despite the scarcity of the juvenile studies, some authors had reported that menstrual abnormalities in pediatric patients range between 23 and 63% of studied cohorts [
3,
6,
16,
17,
19,
20]. A previous adult study confirmed this finding in up to 50% of lupus cases [
21]. Primary amenorrhoea was observed in 3 of our JSLE patients (14.2%) and 1 JDM girl. The percentage of SLE girls with amenorrhea was 17% in
Medeiros et al., 2009 [
16] cohort and it was 11.7% in another Brazilian group [
20]. Our and
Silva et al., 2002 [
3] studies reported six JSLE patients presented with dysmenorrhea.
The median of the age of menarche for patients with JSLE was similar to JIA and JDM groups; around the age of 12 years. The proportion of girls with delayed menarche was 8.5%. Preceding reports showed that in girls with JIA or JSLE, the menarche and puberty were delayed than in the healthy adolescent [
22‐
24]. It was also observed to be delayed or absent in a high frequency (22%) among JSLE [
25]. The median of the menstrual blood flow was the same in 3 groups (5 days); it was lower in patients with JSLE than healthy control in
Medeiros et al., 2009 [
16] cohort.
In this study, there were 3 JSLE, 2 JIA, and 1 JDM patients with delayed puberty without a statistical difference between the studied groups. The prevalence of children with delayed puberty was 15% and sexual maturity was retarded for all types of JIA as shown by
Maher et al., 2013 [
22]. On the other hand, the percentage of females with delayed puberty was 36.1% in
Rygg et al., 2012 [
25] longitudinal cohort analysis. Meanwhile, another study demonstrated that the patterns of pubertal changes were similar in JSLE and control [
16].
We observed that the median of SLICC/ACR damage index was statistically higher in JSLE with abnormal menstrual cycles, but the SLEDAI-2 K did not reach statistically significant difference. However, the disease activity nor damage index related to the menstrual disturbance in JIA or JDM cases. Formerly, it was noted that the medians of SLEDAI-2 K and SLICC-ACR/DI were also similar in JSLE patients with menstrual abnormalities versus normal cycles [
3,
16]. While, it was demonstrated previously that the menstrual disturbances were related to the disease activity parameters [
26].
The cumulative steroid dose was much higher in those with menstrual abnormalities versus regular cycles (p < 0.05) in JSLE girls that was statistically differ than JIA or JDM cases supporting the previous observations [
24‐
26]. Nevertheless, an earlier analysis revealed that no impact of steroid use in girls with JIA concerning the age of menarche as compared to the healthy controls [
23]. No association between CYC use or its cumulative dose and menstrual abnormalities was demonstrated in the previous reports [
3,
16,
20] as also observed in our research. This finding may be attributed to the minor ovarian damage related to CYC use at this age category. The estimated risk of amenorrhea in females less than 25 years ranges between 0 and 11% [
14,
27]. Moreover, the small sample size may impair a definitive conclusion regarding this point.
No significant differences were found in the other lines used in the 3 diseases between those with menstrual abnormalities versus normal cycles. The dose and duration of immunosuppressive agents were not related to the onset of puberty or gonadal function as stated by
El Badri et al., 2014 [
24].
In our cohort, a limited number of cases exhibited alternation of hormonal profiles. The median of FSH, LH, E2, and prolactin were comparable in all studied groups and in those with menstrual disturbances or regular cycles.
Ronchezel et al., 2001 [
28] showed that the serum prolactin was normal in JSLE patients. Moreover,
Silva et al., 2002 [
3] confirmed that most cases with JSLE had normal hormonal profile. The presence of normal hormonal profile during the follicular phase may indicate a normal ovarian reserve.
The FSH is the most sensitive marker of ovarian function [
29] and its level was comparable between those with or without menstrual abnormalities in JSLE as reported before [
16]. Meanwhile, LH was found to be low in the adolescent lupus patients in
Medeiros et al., 2009 [
16] study. The US diameters of the endometrium and ovarian volumes were comparable in all our groups likewise a former analysis [
3].
No statistical correlation was detected between the age of the menarche of our cases and the studied parameters except for the age at puberty onset in all groups and the disease duration in JIA cohort. Despite of being similar between those with menstrual abnormalities and normal cycles in
Silva et al., 2002 [
3] research, the disease duration and cumulative dose of prednisone showed a linear correlation with the age of menarche. These variables may be dependent on the delayed menarche of these cases.
The SLICC/ACR damage index was the significant predictor of menstrual abnormalities in JSLE patients rather than the cumulative steroid use or disease duration. Nevertheless, this finding should be considered with caution owing to the limited sample size of JSLE. Our study had some limitations as self-reporting of some variables as age of menarche, days of menstrual flow, the small sample size, and the lack of reference group for comparison. Therefore, a long-term study with a larger sample size is fundamental to confirm our findings.
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