Autoimmune polyglandular syndrome type 3 (APS-3) among patients with premature ovarian insufficiency (POI)

European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 61–65

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Autoimmune polyglandular syndrome type 3 (APS-3) among patients with premature ovarian insufficiency (POI) Katarzyna Szlendak-Sauer a, Daniel Jakubik a, Michał Kunicki a,b,*, Jolanta Sko´rska a, Roman Smolarczyk a a b

Department of Gyneacological Endocrinology, Medical University of Warsaw, Ul. Karowa 2, 00-315 Warsaw, Poland INVICTA Fertility and Reproductive Centre, 00-019 Warsaw, Poland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 9 March 2016 Received in revised form 25 April 2016 Accepted 13 May 2016

Objectives: Autoimmune polyglandular syndrome type 3 – (APS-3), is defined as the coexistence of autoimmune thyroiditis with other non-ovarian autoimmune diseases without primary adrenal insufficiency. Additionally the definition of APS-3 also includes primary ovarian insufficiency (POI) coexistence with autoimmune thyroiditis. The main goal of that study is to assess the prevalence of APS-3 defined as coexistence of autoimmune thyroiditis with POI in population of 46 XX karyotype women with primary ovarian insufficiency (POI). The second goal is to investigate hormonal profile and insulin sensitivity in women with POI and subgroups of women with APS-3 – POI/APS-3(+) and without APS 3 – POI/APS-3(). Materials and methods: Anthropometric measurements, coexistence of autoimmune diseases, androgens, fasting glucose and insulin, glucose and insulin at 600 and 1200 of oral glucose tolerance test (OGTT) and homeostasis model for insulin resistance (HOMA-IR), were determine in 98 patients aged between 18 and 39 with spontaneous 46 XX primary ovarian insufficiency (POI), in 33 POI/APS-3(+), 65 POI/APS3(), and 75 healthy controls. Results: Continuous data were summarized by the mean  standard deviation (SD), and categorical data by number (percentages). Data were checked for normality using Shapiro–Wilk test, the comparison between groups were performed using non-parametric Mann–Whitney or Kruskall–Wallis test. Pearson’s correlation coefficient was used to assess the relationships between parameters. Statistical significance was defined as p values <0.05. Autoimmune thyroid disease (ATD) was presented in 33/98 (33.7%) patients with POI. The groups did not differ significantly in respect to age and body mass index (BMI). Women with POI, POI/APS-3(+) and POI/APS-3() showed significantly lower serum androgens in comparison to controls. Additionally women with POI/APS-3(+) showed hyperinsulinemia after 1 h of OGTT; No significant differences in serum fasting glucose, insulin and during 2 h OGTT between groups were observed. Conclusions: The prevalence of APS-3 is 33.7% in patients with spontaneous 46 XX primary ovarian insufficiency. Women with POI, POI/APS-3(+) and POI/APS-3() feature lower testosterone, androstendione, dehydroepiandrostendione sulphate in comparison to controls. Women with POI/APS-3(+) could have hyperinsulinemia and should be carefully evaluated for metabolic disorders. ß 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Premature ovarian insufficiency (POI) Premature ovarian failure (POF) Autoimmune polyglandular syndrome (APS) Autoimmune thyroid disease (ATD) Hashimoto’s thyroiditis

Introduction Autoimmune polyglandular syndromes (APSs) are constellations of multiple endocrine gland insufficiencies. The frequent finding of combined manifestations of autoimmune diseases

* Corresponding author at: INVICTA Fertility and Reproductive Centre, 00-019 Warsaw, Poland. E-mail address: [email protected] (M. Kunicki). http://dx.doi.org/10.1016/j.ejogrb.2016.05.023 0301-2115/ß 2016 Elsevier Ireland Ltd. All rights reserved.

described by Neufeld et al. [1] in 1980 led to a classification of APSs which comprises: APS-1 (primary adrenal insufficiency, mucocutaneous candidiasis and hypoparathyroidism), APS-2 (primary adrenal insufficiency with autoimmune thyroid disease and/or diabetes mellitus type 1) [2]. It is important to point out that these diseases are characteristic for APS-1 and 2 but in both types many other diseases can also exists (e.g. alopecia, vitiligo). Autoimmune polyglandular syndrome type 3 (APS-3) is an occurrence of autoimmune thyroiditis accompanied by other organ non-ovarian specific autoimmune disorders in the absence

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K. Szlendak-Sauer et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 61–65

of adrenal insufficiency. To date, quite a few of multifarious comorbidities were described including: diabetes mellitus, vitiligo, alopecia, coeliac disease, Crohn’s disease, primary biliary cirrhosis, pernicious anemia, multiple sclerosis, rheumatoid arthritis and myasthenia gravis [3]. The APS-3 also includes autoimmune gonaditis and hypergonadotropic hypogonadism as part of their repertoire of expressed diseases; however it is unclear whether unexplained ovarian insufficiency is autoimmune in nature [4]. The fourth type of APS (APS-4) involves autoimmune adrenal insufficiency with other autoimmune endocrine gland disorder but does not fulfill the criteria of APS 1-3 [2,3]. Premature ovarian insufficiency (POI) is a heterogeneous disease defined as sustained oligo/amenorrhoea of at least 4 months duration with concomitant elevated levels of gonadotropins (FSH >40 mIU/ml) and sex steroid deficiency in women aged before age 40 years [5]. It is estimated to affect about 1% of women younger than 40, 0.1% of under 30 and 0.01% of women under the age of 20 [5]. It has long been recognized that POI occurs in 40–60% of APS-1 (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) and in 10–25% of APS-2 [4,5]. POI is frequently associated with autoimmune disorders (10–30%), particularly hypothyroidism (25%), Addison’s disease (3%) and diabetes mellitus (2.5%) [6–8]. There are limited number of studies with regard to APS-3 and POI [9,10]. Thus the main objective of the study is to estimate the prevalence of autoimmune polyglandular syndrome type 3 (APS3), in 46 XX karyotype women diagnosed with primary ovarian insufficiency (POI). The second goal is to investigate hormonal profile and insulin sensitivity in POI group and subgroup of women with APS-3 Materials and methods Study population Eligibility criteria for the inclusion of patients to POI study group were defined as women before age 40 years with oligomenorrhoea/amenorrhoea lasting 4–6 months, FSH >40 IU/ L (at least two measurements over 1 month apart) and estradiol level <20 pg/ml [5]. A history of iatrogenic ovarian damage, chemotherapy, pelvic surgery and/or radiotherapy and metabolic diseases were the exclusionary factors. Similarly, patients with primary amenorrhoea, abnormal karyotype (45, XO, other sex chromosome anomalies, premutation of FMR1 gene) have not been taken into consideration in this study. Controls The controls were healthy, non-pregnant and regularly menstruating women. Accordingly, women who were on chronic medications and hormonal contraception in the past 6 months prior to enrollment to the study were excluded. Laboratory data Case history, clinical data (age, height, weight), physical and gynecological examination including transvaginal pelvic ultrasound (7.5 MHz vaginal probe, Hitachi Aloca UST 9130 sonograph) and ultrasonography of thyroid (10.0 MHz probe, Hitachi Aloca UST 9130 sonograph) were carried out in all women of the study group. Body mass index (BMI) was calculated as weight (kg)/height (m2) [8].

Laboratory data included serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), thyroid-stimulating hormone (TSH), free thyroxine (fT4), antithyroid peroxidase antibodies (anti-TPO), anti thyroglobulin antibodies (anti-TG), androstenedione (A), dehydroepiandrostenedione sulphate (DHEAS), total testosterone (T), sex hormonebinding globulin (SHBG), plasma cortisol 8.00 am and 11.00 pm. Free Androgen Index (FAI) was calculated as [T/SHBG  100%] [11]. Glucose and insulin at 00 , 600 , 1200 of oral 75 g of glucose tolerance test (OGTT) was also taking into consideration. Insulin resistance was determined using the homeostasis model for insulin resistance (HOMA-IR) calculation [fasting insulin  fasting glucose/22.5] [11]. Impaired fasting glucose (IFG) was defined as glucose between 100 and 125 mg/dl. Impaired glucose tolerance test (IGT) was defined as a two hour post-challenge blood glucose between 140 and 199 mg/dl. Diabetes when: (a) fasting glucose 126 mg/dl, (b) random plasma glucose 200 mg/dl with typical symptoms or (c) a 2-h 200 mg/dl during 75-g OGTT [11]. Hyperinsulinemia was defined according to Ten’s study (fasting insulin >15 IU/ml, or >150 IU/ml after 1 or >75 IU/ml after 2 h of OGTT) [12]. In the POI group blood samples were collected in any convenient day, in the control group – during the early follicular phase of menstrual cycle (days 3–6). Assays The laboratory parameters included FSH and TSH were measured using Enzyme Linked Fluorescent Assay (VIDAS, BioMerieux). Serum anti-TPO and anti-TG levels were measured by electrochemiluminescence immunoassay ECLIA (Elecsys and Cobas e analyzers, Roche). Serum anti-TPO level greater than 34 IU/ml and anti-TG >4.11 were considered positive. Our laboratory normal range during follicular phase for FSH was 3.03–8.08 mIU/ml, LH 1.8–11.78 mIU/ml, estradiol 21–251 pg/ml, prolactin 5–35 ng/ml,testosterone 0.1–0.56 ng/ml,androstendione 0.3–3.5 ng/ml, SHBG 19.84–155.2 nmol/L, DHEAS 2.68–9.23 umol/ L, TSH 0.35–4.94 uIU/ml. Statistical analysis Statistical analysis was performed using the R version 3.0.1 (Copyright (C) 2013 The R Foundation for Statistical Computing). Continuous data were summarized by the mean  standard deviation (SD), and categorical data by number (percentages). Data were checked for normality using Shapiro–Wilk test, which revealed that in the vast majority of variables a distribution was not normal. Therefore, in further calculations non-parametric Mann–Whitney or Kruskall–Wallis test were performed. For data with normal distribution the ANOVA test was performed. Additionally for those data with significant differences post-hoc Dunn or Games–Howell tests were performed. Pearson’s correlation coefficient was used to assess the relationships between parameters. Statistical significance was defined as p values <0.05. Results A retrospective study included 98 patients with spontaneous 46 XX premature ovarian insufficiency (POI), aged between 18 and 39, (mean 30  6.3) referred to the Department of Gynecological Endocrinology of Medical University of Warsaw, between 2010 and 2015. The number of the participants in the control group was 75 women, aged 19–39, (mean 29.4  4) years. Based on clinical characteristics of 98 enrolled women with premature ovarian insufficiency (POI), the mean age of subgroup of

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women with POI/APS-3(+) was 30.5  6.0 years and women with POI/APS-3() 30.4  6.1 years. The mean age of women in control group was 29.4  4 years. The mean body mass index (BMI) was 23.5  2.8 kg, 23.04  2.82, 23.8  2.75 in the POI, POI/APS-3(+), and POI/APS-3() respectively. The mean BMI was 23.2  2.5 kg/m2 in control group. There were no statistically significant differences between the study and control group with regard to age, and BMI (p < 0.05). None of the patients with POI had clinical features of adrenal insufficiency and plasma cortisol concentrations measured in the morning (8 am) and late in the evening (11 pm) were within their normal ranges in all of them (13.18  3.48 and 2.7  1.51 respectively). Coexistence of POI and autoimmune thyroid disease (ATD) as autoimmune polyglandular syndrome type 3 (APS-3) has been reported in 33/98 (33.7%) cases. Nodular goiter was noted in 6/98 (6.1%) POI women. Furthermore, one patient was operated on mediastinal thymoma and two – because of nodular goiter. In the POI group there were also found several autoimmune comorbidities: vitiligo in 3/98 (3.06%) patients, alopecia in 2/98 (2.04%), Crohn’s disease in 2/98 (2.04%), colitis ulcerosa in 1/98 (1.02%) and myasthenia gravis in 1 (1.02%) patient. We found positive auto-antibodies against thyroid-specific peroxidase (anti-TPO) in 10/75 (7.5%) of women in the control group. Any women presented clinical and hormonal feature of Graves’s disease. Additionally during the hormonal assessment of the patient any women were treated with levothyroxine. The main hormonal parameters within the POI study and control groups are presented in Table 1. The mean serum FSH, LH and estradiol levels were 73.9  26.8, 36.99  15.3 IU/l, and 14.5  8.4 pg/ml, 5.13  1.09, 5.7  2.26 and 44.5  35.6 pg/ml in the POF and control groups respectively (p < 0.001). Furthermore, 18/98 (18.4%) patients from POI group and 11/75 (14.6%) from controls had hyperprolactinemia. Women with POI presented significantly lower T, A, DHEAS and PRL levels than controls. We found no significant differences in calculated free androgen index (FAI) and SHGB between the two groups.

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There were no significant differences between two groups in serum fasting glucose, and insulin and 1 or 2 h after OGTT. Hyperinsulinemia during OGTT was noted in 21/98 (21.4%). Insulin resistance quantified by HOMA-IR revealed no significant differences between POI and control group. Hormonal and metabolic parameters of subgroups with, POI/APS-3() are presented in Table 2. Among 98 patients with POI there were 33 women with autoimmune thyroid disease (ATD) classified as the POI/APS-3(+) subgroup to analyze the hormonal profile and insulin sensitivity. There were significantly lower serum T, A and DHEAS levels in women with POI/APS-3(+) than in healthy controls. In opposite to POI study group the serum insulin was significantly higher in 1 h of OGTT in comparison to POI/APS3() and controls. Additionally, the POI/APS-3(+) subgroup presented lower serum SHBG levels compared to control group. The serum fT4 levels were positively correlated with SHGB concentrations in the POI/APS-3(+) subgroup. We also found positive correlations between BMI and insulin after 2 h of OGTT in POI group (r = 0.48, p = 0.02). Discussion The autoimmune etiology may be responsible in up to 30–50% of women with POI [13]. However, evaluation the causes of POI in majority of cases still remains impossible. If we exclude the iatrogenic and surgery causes, metabolic diseases (galactoseamia), as well as we obtain normal 46 XX karyotype without FMR1 premutation gene, we will suspect ovarian autoimmunity as a potential cause of POI [14,15]. Coexistence of autoimmune diseases of the thyroid, adrenal gland and diabetes mellitus leads to recognition of the autoimmune polyglandular syndrome (APS) [16]. In view of the widespread availability of anti-thyroid antibodies assays, autoimmune thyroid disease is predominately (5–10%) diagnosed in the female population [17]. In the current study, we diagnosed autoimmune thyroid disease in 33 (33.7%) karyotypically normal women with POI compared to 6.7% of regularly cycling controls. Furthermore, we reported the

Table 1 Hormonal parameters of women with primary ovarian insufficiency (POI) and control group. POI (N = 98) Mean  SD Total T (ng/ml) SHBG (nmol/L) FAIa A (ng/ml) DHEAS (mmol/l) TSH (mlU/l) ft4 pmol/l PRL (ng/ml) OGTTb (mg/dl) OGTT1hc (mg/dl) OGTT2hd (mg/dl) Ins0he (IU/ml) Ins1 (IU/ml) Ins2h (IU/ml) HOMAf a b c d e f *

0.39  0.24 50.48  26.6 3.23  2.22 2.38  1.11 5.911  3.12 2.71  6.81 12.08  2.74 31.2  12.19 86.51  7.81 145.27  38.52 107.21  29.78 6.54  3.68 61.13  53.39 39.77  36.05 1.31  0.64

P value*

Control group (N = 75) Range 0.1–1.8 11.6–143 0.6–11.3 0.3–5 0.1–16.24 0.2–53.5 0.77–17.1 15.3–100.6 67–111 15–256 41–189 1.8–17.9 11.40–390 10.2–235 0.3–3.56

Median

Mean  SD

Range

Median

0.33 44.3 2.65 2.4 5.69 1.4 12.35 28.3 86.0 142.5 105.5 5.85

0.45  0.19 59.3  30.9 3.38  2.66 3.28  1.2 7.2  2.9 0.44  0.19 13.26  1.51 36.3  13.7 84.55  6.8 145.83  36.32 105.82  27.87 6.0  2.87

0.16–1.31 17.9–161 0.5–14.3 1.1–6.9 1.1–16.5 0.16–1.3 9.7–17.08 12.8–89.5 70–111 70–220 111–191 1.2–14.2

0.44 55 2.43 3.15 6.85 0.44 13.09 33.6 85 145 105 5.3

3.80–120 7.7–118.2 0.30–3.56

46.2 33 1.26

50.75 31.05 1.26

FAI, free androgen index. OGTT, oral glucose tolerance test, fasting serum glucose. OGTT, 1 h. OGTT, 2 h. Insulin measured before the OGTT. HOMA, homeostatic model assessment. P-value comparing the POI subgroup to control group, according to the Mann–Withney test.

48.1  26.6 39.8  23.9 1.31  0.64

0.005 NS NS <0.001 <0.001 NS 0.01 0.001 NS NS NS NS NS NS NS

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Table 2 Hormonal and metabolic parameters of subgroups with POI/APS-3(+), POI/APS-3(), and control group. POI/APS-3(+) (N = 33)

FSH (mIU/ml) LH (mIU/ml) E2 (pg/ml) Total T (ng/ml) SHBG (nmol/L) FAIa A (ng/ml) DHEAS (mmol/l) TSH (mlU/l) ft4 (pmol/l) PRL (ng/ml) OGTTb (mg/dl) OGTT1hc (mg/dl) OGTT2hd (mg/dl) Ins0he (IU/ml) Ins1 (IU/ml) Ins2h (IU/ml) HOMAf a b c d e f *

POI/APS-3() (N = 65)

P-value*

Control group (N = 75)

Mean  SD

Range

Mean  SD

Range

Mean  SD

Range

68.44  26.13 33.69  15.42 14.20  8.15 0.35  0.17 42.23  17.87 3.29  2.00 1.90  0.96 5.20  2.63 5.02  11.10 12.19  3.02 28.62  9.86 86.02  7.42 141.65  40.01 106.50  32.65 7.64  4.17 78.45  76.45 51.35  56.33 1.67  0.89

22.01–131 9.5–69.4 5.0–52.0 0.1–0.84 11.6–89.2 0.9–7.5 0.3–3.8 0.1–16.24 0.2–53.5 0.77–17.1 9.2–50.6 74–107 15–256 42–189 1.8–17.2 22.4–390 10.4–235 0.41–3.6

76.79  26.45 38.73  14.85 14.76  8.57 0.41  0.27 54.8  29.54 3.2  2.33 2.68  1.10 5.74  2.67 1.49  0.81 11.17  3.40 31.2  12.19 86.7  8.05 147.5  37.8 107.65  28.19 5.9  3.24 52.8  36.06 34.23  18.91 1.31  0.77

40–165 9.2–68 5.0–67.0 0.12–1.8 18.50–143.0 0.6–11.3 0.66–5.0 1.1–11.9 0.35–4.7 0.5–17.0 15.3–100.6 67–111 61–237 41–176 2.4–17.9 11.4–193.8 10.2–82 0.46–3.90

5.13  1.09 5.7  2.26 44.51  35.57 0.44  0.19 59.27  30.91 3.38  2.66 3.28  1.20 7.17  2.91 0.44  0.19 13.26  1.51 36.3  13.7 84.55  6.8 145.83  36.32 105.82  27.87 6.00  2.87 48.05  26.62 39.83  23.94 1.31  0.64

3.1–9 2–10.4 20–303 0.16–1.3 17.90–161 0.50–14.3 1.00–6.9 1.1–16.5 0.16–1.3 9.7–17.08 12.8–89.5 70–111 70–220 111–191 1.2–14.20 3.80–120 7.70–118.20 0.30–3.56

<0.001 <0.001 NS NS NS NS <0.001 0.001 0.036 0.001 0.002 NS NS NS NS 0.05 NS NS

FAI, free androgen index. OGTT, oral glucose tolerance test, fasting serum glucose. OGTT, 1 h. OGTT, 2 h. Insulin measured before the OGTT. HOMA, homeostatic model assessment. P-value comparing the POI/APS(+), POI/APS(), and control group, according to ANOVA or Kruskall–Wallis test.

concomitance of other autoimmune diseases including vitiligo in 3/98 (3.06%) patients, alopecia in 2/98 (2.04%), Crohn’s disease in 2/98 (2.04%), colitis ulcerosa in 1/98 (1.02%) and myasthenia gravis in 1 (1.02%) patient. Petrikova et al. [18] presented autoimmune thyroid disease in 14–27% of women with POI. Consequently, the risk for autoimmune diseases in women with POI is higher than in general population, suggesting that there may be a still unknown autoimmune component [19]. According to Nelson et al. [20] approximately 20% of women with spontaneous POI develop autoimmune hypothyroidism. Autoimmune-mediated oophoritis can be confirmed histologically when POI is found among patients with adrenal autoimmunity [21]. Most probably, it is the result of a process caused by antibodies against common antigens between the two glands both constituted by steroidogenic cells [22]. Anti-ovarian antibody testing was not performed in our study, although some POI diagnostic algorithms propose determination of adrenal and ovarian autoantibodies [23]. Antibodies to several ovarian antigens (LH receptor, FSH receptor, zona pellucida) have been proposed as markers of ovarian autoimmunity, however the association of these antibodies with POI has not been confirmed in other studies [24]. Moreover, poor predictive value and specificity of ovarian antibody test makes it unreliable to use in the diagnosis of autoimmune POI [25,26]. Ovarian biopsy is essential for the diagnosis of autoimmune oophoritis [27], although Bakalov et al. [21] has shown autoimmune oophoritis only in 4% of APS 2. In spite of a comparable age of the study and control groups we observed decreased levels of adrenal androgens: androstenedione (A) and DHEAS in POI women. There were no deficiency of cortisol and clinical symptoms of Addison’s disease in our study however patients with a diagnosis of autoimmune POI requires further screening for autoimmune adrenal insufficiency [16]. Benetti-Pinto et al. [28] noted lower A and DHEAS concentrations in 30 women with POI compered to regularly menstruating women. However, these results were not statistically significant, probably as a result of small study group. Whereas, Ott et al. [17] observed decreased DHEAS levels in women with POI and Hashimoto’s thyroiditis.

The available literature documented clinical consequences of androgen deficiency for young POI women on bone mineral density, sexual function quality of life [29]. Additionally, the POI/APS-3(+) subgroup presented lower serum hormone binding globulin (SHBG) levels compared to control group but it did not reach significance in our study population. Fluctuation of SHBG concentrations is observed in women with thyroid dysfunction (SHBG as a marker of hyperthyroidism). In our study there was correlation between SHBG and fT4 in patients with autoimmune thyroid disease although the study population was clinically and biochemically euthyroid. An unexpected finding of our study was hyperinsulinemia noted after 1 h of OGTT in the POI/APS-3(+) subgroup. We did not observed such results in POI group when compared to control. We can speculate that women with POI/APS-3(+) are more predisposed to hyperinsulinemia and should be carefully evaluated. Additionally we found hyperprolactinemia both in women with POF as in control group. In all cases the magnetic resonance of pituitary revealed no signs of adenoma or other central nervous system mass lesion. Moreover we found no cases of macroprolactinemia in these women. Thus we can speculate that higher prolactin levels was caused by stress or other unknown factors. There was no insulin resistance evaluated in HOMA IR, probably because of the normal BMI of the study and control groups. Similarly, Ates et al. [30] found no difference in fasting serum levels of glucose, insulin and HOMAIR between the POI and control groups. Additionally, they pointed out that POI is associated with increased risk of metabolic syndrome, independently of obesity. To our knowledge, the studies concerning the assessment of glucose metabolism and insulin resistance in POI women are limited. The data published in the available literature revealed that young women with spontaneous POI were generally less obese than the population-based norms for the same countries [13]. Despite the fact that POI does not seem to be associated with increased BMI, patients exhibits a significantly higher risk for cardiovascular disease. Estrogen and SHBG deficiency, visceral fat distribution, hyperinsulinemia or atherogenic lipid profile

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contributes to a high relative risk for atherosclerosis in young POI women [13]. The coexistence of autoimmune diseases in patients with POI increases the risk of osteoporosis, cardiovascular and genitourinary disorders [13]. The strengths of this study is a large population of women with POI/APS-3(+). Additionally we evaluated not only hormonal profile but also insulin sensitivity in women with POI and subgroup of women with POI/APS-3(+). We can speculate that not only glucose but also OGTT with insulin could be rationale to measure in women with POI. Further studies are needed in this field. Conclusions The results of our study revealed the prevalence of autoimmune polyglandular syndrome type 3 is 33.7% in patients with spontaneous 46 XX primary ovarian insufficiency. Women with POI, POI/APS-3(+) and POI/APS-3() age and BMI matched controls feature lower testosterone, androstendione, dehydroepiandrostendione sulphate and higher insulin in comparison to healthy subjects. Conflict of interest All the authors declare that there are no conflicts of interest in this manuscript.

Contribution to authorship KS DJ MK JS RS: conception and design of the idea, data interpretation and preparation of manuscript. All the authors conceived and planned the work that led to the manuscript or played an important role in the acquisition, analysis and interpretation of the data. All the authors take responsibility for the work as a whole, from inception to the published manuscript, and will be responsible for sign-off of the final proofs prior to publication

Ethical approval Ethical permission to conduct the study was granted by the Ethics Committee of the Medical University of Warsaw in Poland (AKBE 46/16).

Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Acknowledgements Authors thank BIOSTAT for the statistical analysis.

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