Endocrine DOI 10.1007/s12020-014-0504-7
ORIGINAL ARTICLE
Frequency of nodular goiter and autoimmune thyroid disease in patients with polycystic ovary syndrome Cevdet Duran • Mustafa Basaran • Orkide Kutlu • Zehra Kucukaydin • Suleyman Bakdik • Ferda Sevimli Burnik • Uysaler Aslan • Sami Said Erdem Samil Ecirli
•
Received: 24 October 2014 / Accepted: 5 December 2014 Ó Springer Science+Business Media New York 2014
Abstract Polycystic ovary syndrome (PCOS), and nodular and autoimmune thyroid diseases are frequently seen disorders. Previous studies reported conflicting results regarding possible association between PCOS and thyroid disorders. In this study, we investigated the frequency of autoimmune thyroid disease (AITD) and nodular goiter in patients with PCOS. Seventy-three PCOS patients and 60 age-matched controls were enrolled in the study. In PCOS group, body mass index values (27.45 ± 5.73 vs. 22.55 ± 3.78 kg/m2, p \ 0.001, respectively), systolic [110 mmHg (90–130) vs. 100 mmHg (90–140), p = 0.016, respectively] and diastolic (72.67 ± 6.52 vs. 66.42 ± 8.88 mmHg, p \ 0.001, respectively) blood pressure, waist circumference (86.27 ± 14.41 vs. 78.78 ± 8.87 cm, p \ 0.001, respectively), and homeostasis model assessment-insulin resistance (HOMA-IR) levels (2.96 ± 2.11 and 1.77 ± 0.83 p \ 0.001, respectively) were higher than controls.
However, thyroid nodule frequency was similar in both groups [22 (30.1 %) vs. 12 (20 %)], also thyroid gland volume was not significantly different [9.23 ml (3.08–32.40) vs. 8.52 ml (4.28–50.29)] among groups. The percentages of patients with thyroid parenchymal heterogeneity, positive anti-thyroid peroxidase, anti-thyroglobulin, and AITD were similar. Cases were reclassified according to the presence of thyroid nodule in which similar HOMA-IR levels were detected (median 2.39 and 1.89, p = 0.093, respectively) despite the fact that the group with nodules had higher mean age (26.5 (18–37) vs. 21 (18–34), p = 0.013, respectively). Similar ratios of thyroid nodule and AITD were found in patients with PCOS and controls. Keywords Polycystic ovary syndrome Thyroid nodule Autoimmune thyroid disease
Introduction C. Duran (&) F. S. Burnik Division of Internal Medicine, Endocrinology and Metabolism, Konya Training and Research Hospital, 42100 Konya, Turkey e-mail: [email protected] M. Basaran Z. Kucukaydin Division of Obstetrics and Gynecology, Konya Training and Research Hospital, Konya, Turkey O. Kutlu U. Aslan S. Ecirli Division of Internal Medicine, Konya Training and Research Hospital, Konya, Turkey S. Bakdik Division of Radiology, Konya Training and Research Hospital, Konya, Turkey S. S. Erdem Department of Biochemistry, Konya Training and Research Hospital, Konya, Turkey
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women and its prevalence is reported as 5–10 % worldwide [1–3]. The characteristics of this syndrome are hirsutism, hyperandrogenism, menstrual disturbance, and infertility. Obesity, impaired glucose tolerance, and insulin resistance are wellknown features of this syndrome [1, 4, 5]. Nodular goiter and autoimmune thyroid disease (AITD) are also frequently seen endocrinological abnormalities [6]. Ultrasonography (USG) and autopsy series indicated a high prevalence of thyroid nodules (19–50 %) in general population [7, 8]. Although associated with well-known risk factors such as age, female gender, and iodine deficiency, exact pathogenesis remains obscure. Similar to nodular goiter, AITD is also frequently seen in reproductive women that may be due to the
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influence of hormonal and chromosomal factors in the etiology [9]. Previous studies reported a possible association between thyroid nodules and insulin resistance which is also proposed to be a risk factor for the development of cancer [10, 11]. To support this hypothesis, insulin-resistant conditions such as acromegaly [12], acrochordons [13], and metabolic syndrome [14], are known to be associated with increased risk of nodule development that also reversed with metformin treatment [15]. Insulin resistance and increased LH/FSH ratio are characteristic features of PCOS [16]. In addition to insulin resistance, the presence of increased LH/FSH ratio may also contribute to the development of goiter through the effect of increased LH on TSH receptors [16–18]. Despite the presence of opposing opinions [19, 20], majority of previous studies that were reported confirmed the coexistence for PCOS with nodular goiter and AITD [21–24]. In this study, we aimed to investigate goiter and AITD frequency in patients with PCOS.
Material and method This prospective study was conducted at Konya Training and Research Hospital, a tertiary care hospital, Clinics of Internal Medicine (Division of Endocrinology) and Obstetrics and Gynecology, between July 2013 and February 2014. Informed consent was taken from all participants. Study protocol was approved by Ethics Committee of Necmettin Erbakan University. Eighty-nine patients with PCOS ages between 18 and 40 were screened for the study and 73 of them enrolled in the study. Age-matched women without PCOS were used as controls. Diagnosis of PCOS was based on Rotterdam criteria with patients meeting at least two of three criteria; first, oligomenorrhea (cycles lasting longer than 35 days) or amenorrhea (less than 2 menstrual cycles in the past 6 months), second, clinical or biochemical hyperandrogenism, and third, polycystic appearance of ovary on USG and the exclusion of other causes of hyperandrogenism, such as Cushing’s syndrome, congenital adrenal hyperplasia, or virilization [15]. Subjects taking drugs in the last 6 months that may interfere with thyroid function tests (except from thyroid hormone and anti-thyroid drugs) or effecting on insulin resistance, such as estrogens, oral contraceptives, corticosteroids, immunosuppressants were excluded from the study. After enrollment, physical examination was performed and all data were recorded on patient forms. Height (m) and weight (kg) were measured with underwear clothing. Waist circumference was measured as the minimum size between iliac crest and lateral costal
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margin. Body mass index (BMI) was calculated as weight (kg) divided by height square (m2). Glucose, insulin, thyroid-stimulating hormone, free thyroxine, anti-thyroglobulin (anti-Tg), and anti-thyroid peroxidase (anti-TPO) autoantibodies were measured using fasting venous blood from the antecubital vein. Insulin resistance was calculated by homeostasis model assessment-insulin resistance (HOMA-IR) (fasting plasma glucose (mmol/l) 9 fasting serum insulin (lIU/ml)/22.5). All samples were taken after an overnight fasting and separated by centrifugation and stored in deep freezer at -70 °C until used for analysis. Fasting glucose levels (normal range (NR): 70–105 mg/ dl) were measured by Abbott C-16000 Autoanalyzer (Abbott Laboratories, Abbott Park, IL) with glucose oxidase method. Free T4 (NR 0.89–1.76 ng/dl), insulin (NR 3–25 mU/l), TSH (NR 0,35-5.5 lIU/ml) were measured by Advia Cetaur XP (Siemens Healthcare Diagnostics, Siemens AG, Germany) with chemiluminescence method; anti-thyroglobulin (anti-Tg) (NR 0–40 IU/ml) and anti-thyroid peroxidase (anti-TPO) (NR 0–40 IU/ml) autoantibodies were measured by Immulite 2000 (Siemens Healthcare Diagnostics, Siemens AG, Germany) with chemiluminescence method. Intra- and inter-assay CVs for TSH were 2.44 and 3.44, for free T4 were 1.77 and 2.9, and for insulin 4.6 and 5.9, respectively. Analytical sensitivity and intra-assay CV for anti-TPO were 5.0 IU/ml and 6.2, and for anti-Tg Ab 5.0 IU/ml and 5.9, respectively. Anti-TPO and anti-Tg autoantibodies concentration exceeding 40 IU/ml were considered positive. Thyroid USG examination was performed using the 5–13 MHz linear probe (Siemens Acuson Antares, Siemens AG, Germany). Assessment of the presence of nodules and parenchymal patterns were recorded on patients’ charts. All the USG nodular lesions measuring over 3 mm were considered as nodule. Thyroid volume was calculated by the elliptical shape volume formula (0.479 9 length 9 width 9 height) for each lobe and the sum of right and left thyroid lobe volume were calculated as total thyroid volume [10]. Statistical analysis Continuous variables were expressed as median (minimum–maximum) or mean ± standard deviation while categorical variables were presented as frequency and related percentage values. Mann–Whitney U test and independent samples t test were used for comparing groups. Chi-square test with Yates correction, Fisher’s exact test, and Fisher–Freeman–Halton test were used to compare categorical variables. Spearman’s correlation coefficient was used to analyze relationship between continuous variables and SPSS for Windows version 21 (IBM
Endocrine
Inc.) was used for recording and analysis of data. Statistical significance level was set at 0.05.
Results Clinical characteristics of patients are summarized in Table 1. In PCOS group, BMI values, (27.45 ± 5.73 and 22.55 ± 3.78 kg/m2, respectively, p \ 0.001), systolic [110 mmHg (90–130) vs. 100 mmHg (90–140), respectively, p = 0.016] and diastolic (72.67 ± 6.52 vs. 66.42 ± 8.88 mmHg, respectively, p \ 0.001) blood pressure, waist circumference (86.27 ± 14.41 vs. 78.78 ± 8.87 cm, respectively, p \ 0.001), and HOMA-IR Table 1 Sociodemographic and study parameters among groups PCOS group (n = 73)
Controls (n = 60)
p value
Age (year)
22 (18–37)
20.50 (19–35)
Height (m)
1.62 ± 0.06
1.63 ± 0.05
Weight (kg)
72.14 ± 16.39
59.67 ± 9.13
\0.001
Body Mass Index
27.45 ± 5.73
22.55 ± 3.78
\0.001
Systolic blood pressure (mmHg)
110 (90–130)
100 (90–140)
0.016
Diastolic blood pressure (mmHg) Waist circumference (cm)
72.67 ± 6.52
66.42 ± 8.88
\0.001
86.27 ± 14.41
78.78 ± 8.87
\0.001
Ferriman–Gallwey score
20 (8–32)
4.50 (1–8)
\0.001
Presence of oligoanovulation
63 (86.30)
0
\0.001
Ultrasonographic polycystic ovary appearances
58 (79.50)
0
\0.001
Glucose (mg/dl)
87.82 ± 10.84
82.08 ± 8.11
Insulin (lIU/ml)
13.42 ± 7.89
8.76 ± 4.01
\0.001 \0.001
0.785 0.356
0.001
HOMA-IR
2.96 ± 2.11
1.77 ± 0.83
TSH (lIU/ml)
2.09 (0.67–16.51)
1.96 (0.01–7.08)
0.397
Free T4 (ng/dl)
1.19 (0.73–1.84)
1.19 (0.81–1.99)
0.543
Anti-TPO positive patients
12 (16.40)
10 (16.70)
1.00
Anti-Tg positive patients
8 (11)
12 (20)
0.227
Anti-thyroid drug treatment
3 (4.10)
0
0.252
L-Thyroxine treatment Thyroid nodule
6 (8.20) 22 (30.10)
1 (1.70) 12 (20)
0.128 0.257
Heterogenous thyroid parenchyme
20 (27.40)
9 (15)
0.131
Total thyroid volume (ml)
9.23 (3.08–32.40)
8.52 (4.28–50.29)
0.539
Values were expressed as mean ± SD, mean (minimum–maximum), or n (%). HOMA-IR homeostasis model assessment-insulin resistance
levels (2.96 ± 2.11 vs. 1.77 ± 0.83 respectively, p \ 0.001) were higher than controls. Mean TSH, free thyroxine levels, the percentage of antiTPO [12/73 (16.4 %) and 10/60 (16.7 %), p = 1.0, respectively] and anti-Tg [8/73 (11 %) and 12/60 (20 %), p = 0.227, respectively] positive patients, and L-thyroxine or anti-thyroid drugs usage were similar in both groups (Table 1). The percentage of patients with thyroid parenchymal heterogeneity was similar in both groups [in PCOS group 20/73 (27.4 %) and in controls 9/60 (15 %), p = 0.131]. In PCOS and controls, thyroid nodule was detected in 22/73 (30.1 %) and 12/60 (20 %) patients (p = 0.26), respectively (Fig. 1). Thyroid gland volume was similar in both groups [in PCOS; median 9.23 ml (3.08–32.40) and, in controls; median 8.52 ml (4.28–50.29), p = 0.539, respectively]. In PCOS groups, 13 patients had single nodule and 9 patients had multiple nodules. In controls, 4 patients had single nodule and 8 patients had multiple nodules. If either thyroid heterogeneity and/or positivity of autoantibodies were considered as AITD, the frequency of AITD was found similar [in PCOS group; 23 (32.5 %) and in controls; 14 (23.3 %), p = 0.394] (Fig. 1). Cases were divided into with- or without thyroid nodule; in cases with thyroid nodule, median age were higher [26.5 (18–37) vs. 21 (18–34), p = 0.013, respectively] and similar HOMA levels were detected (median 2.39 (0.26–8.59) and 1.89 (0.47–14.08), p = 0.093, respectively, Table 2). Correlation analysis revealed a significant positive correlation between the age and the total thyroid volume (r = 0.28, p = 0.001), however, this correlation was not detected between HOMA-IR and thyroid volume (Table 3).
Fig. 1 Thyroid nodule and autoimmune thyroid disorders frequency in patients with- or without polycystic ovary syndrome
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Endocrine Table 2 Age and insulin resistance indices in patients with- or without thyroid nodule Presence of thyroid nodule Yes (n = 34) Age (year)
26.50 (18–37)
Glucose (mg/dl)
87 (71–119)
Insulin (lIU/ml) HOMA-IR
11.40 (1.42–35.50) 2.39 (0.26–8.59)
p value
No (n = 99) 21 (18–34)
0.013
85 (52–133)
0.349
9.29 (2.15–43.30) 1.89 (0.47–14.08)
0.147 0.093
Values are expressed as mean (minimum–maximum). HOMA-IR Homeostasis model assessment-insulin resistance Table 3 Correlation analysis between study parameters n = 133 Age HOMAIR
TSH r
0.02
p
0.805
r
0.08
p
0.351
Total thyroid volume 0.28 0.001 -0.02 0.867
r Spearman’s rank correlation coefficient, TSH thyroid-stimulating hormone, HOMA-IR homeostasis model assessment-insulin resistance
Discussion AITD, nodule frequency, and thyroid volume were similar in patients with- or without PCOS. Additionally, positive correlation was detected between age and thyroid volume. Ultrasonography and autopsy studies report the prevalence of thyroid nodule up to 50 % in elderly patients and in women, and its prevalence increases in iodine-deficient area [7, 8]. In Turkey, iodine prophylaxis was started in 1999 and our region is the mildly iodine-deficient area at the moment (average urinary iodine concentration, 92 lg/l) [25]. There are studies that indicated a relationship between insulin resistance and thyroid nodules in the last decade [10, 12–14, 20]. This causal relationship was confirmed because of reduction in thyroid nodule volume with amelioration of insulin resistance using metformin [15]. Insulin resistance and increased LH/FSH ratio are characteristic features of PCOS [16]. In this respect, we could expect an increased frequency of thyroid nodules in PCOS. However, paucity of studies about this subject is interesting to note. Moreover, current studies have significant methodological drawbacks to show any association. Although, Anaforoglu et al. failed to demonstrate an association between thyroid disorders and PCOS, subgroup analysis after reclassification according to metabolic syndrome revealed an association in PCOS group [20]. Increased antiTPO, anti-TG, thyroid volume, and heterogeneity in metabolic syndrome-associated PCOS patients, lead the authors to hypothesize that the association is related with the presence of metabolic syndrome rather than PCOS per se [20].
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Ayturk et al. also confirmed this hypothesis by demonstrating increased thyroid volume and frequency nodules in their metabolic syndrome patients [14]. Kauchei et al. reported increased goiter frequency in patients with PCOS. A significant limitation of this study is the use of manual examination for the diagnosis of goiter instead of USG which is considered as gold standard [19]. In our opinion, use of manual examination in the study potentially introduced significant bias in the detection of goiter. Despite an increased LH/FSH ratio (1.83 vs. 1.16) and HOMA-IR values (2.96 ± 2.11 vs. 1.77 ± 0.83), our results failed to demonstrate increased nodule frequency and thyroid volume. A lower level of HOMA-IR values compared with previous studies [10, 15] and/or association with metabolic syndrome instead of PCOS could explain this observation. Another important issue is AITD’s association with PCOS. Previous studies reported increased frequency of AITD with higher levels of autoantibodies. However, in the current study, we also failed to demonstrate a difference in anti-TPO and anti-Tg Ab levels among the groups. In a recent meta-analysis that included 6 studies [19–24], Danfeng et al. concluded that current evidence is directed toward and increased AITD frequency in PCOS [26]. Janssen et al. [21] and Sinha et al. [24] reported an increased AITD in PCOS patients. Janssen et al. speculated that hormonal influences (increased estrogen/progesteron levels) might be the cause [21]. Sinha et al. reported a antiTPO mean values of 28.037 ± 9.138 in controls and 25.72 ± 8.27 in PCOS group with a p value of 0.035. However, recalculation of p value with these data reveals a p value of 0.095 which is not significant [24]. On the other hand Ganie et al. [27] reported an increased PCOS frequency in AITD patients. But, we think that this study had significant selection bias in which they included only 13–18 years old girls. The mean age of menarche in their population was 12 years. Therefore, diagnosis of PCOS in this group of perimenarchial school girls was not only difficult but might be inappropriate. Additionally, considering the increasing anti-TPO titers with advancing age, AITD diagnosis in this population was expected to be significantly lower compared with adults. Ott et al., by taking a step further, claimed that anti-TPO titers could be used as a predictor for the success of ovulation induction in their PCOS patients treated for infertility [23]. In another study, published by Garelli et al., it was reported that patients with PCOS have higher AITD frequency than controls (27 vs. 8 %, respectively), but non-thyroid autoantiobodies (against parietal cells, intrinsic factor, adrenal-cortex, 21-hydroxilase, steroid producing cells, side-chain cleavage enzyme, islet-cell, glutamic acid decarboxylase, nuclei, and mitochondria) frequency were similar [22].
Endocrine
Kachuei et al. reported a higher anti-TPO titers in PCOS patients, despite a similar ratio of anti-TPO and anti-Tg positive patients in both groups. A significant drawback of this study is the lack of thyroid USG and antibody titers in some patients [19]. Despite the cumulated positive evidence about the association of AITD and PCOS, we failed to demonstrate this finding in our study groups. Despite an opinion about PCOS as an autoimmune disease [26], there is lack of uniformity in finding autoantibody titers and levels among those in previous studies that apparently included our findings. In our opinion, major drawback of our study might be the sample size, however considering the lack of the uniformity in diagnostic modalities exact calculation of sample sizes might not be possible with the current evidence. Therefore, studies with larger sample sizes with objective and standardized laboratory and imaging modalities were required before final comment on this subject.
Conclusion Our results failed to demonstrate a significant relation between thyroid volume, thyroid nodule, and AITD frequency in patients with- or without PCOS. The increased frequency of goiter and AITD in patient with PCOS may be related to component of metabolic syndrome rather than diagnosis of PCOS. Also suggested by previous studies, evaluation of thyroid nodules should be a part of evaluation of patients with PCOS specifically in cases with associated metabolic syndrome. Conflict of interest interest.
The authors declare that there is no conflict of
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ORIGINAL ARTICLE
Frequency of nodular goiter and autoimmune thyroid disease in patients with polycystic ovary syndrome Cevdet Duran • Mustafa Basaran • Orkide Kutlu • Zehra Kucukaydin • Suleyman Bakdik • Ferda Sevimli Burnik • Uysaler Aslan • Sami Said Erdem Samil Ecirli
•
Received: 24 October 2014 / Accepted: 5 December 2014 Ó Springer Science+Business Media New York 2014
Abstract Polycystic ovary syndrome (PCOS), and nodular and autoimmune thyroid diseases are frequently seen disorders. Previous studies reported conflicting results regarding possible association between PCOS and thyroid disorders. In this study, we investigated the frequency of autoimmune thyroid disease (AITD) and nodular goiter in patients with PCOS. Seventy-three PCOS patients and 60 age-matched controls were enrolled in the study. In PCOS group, body mass index values (27.45 ± 5.73 vs. 22.55 ± 3.78 kg/m2, p \ 0.001, respectively), systolic [110 mmHg (90–130) vs. 100 mmHg (90–140), p = 0.016, respectively] and diastolic (72.67 ± 6.52 vs. 66.42 ± 8.88 mmHg, p \ 0.001, respectively) blood pressure, waist circumference (86.27 ± 14.41 vs. 78.78 ± 8.87 cm, p \ 0.001, respectively), and homeostasis model assessment-insulin resistance (HOMA-IR) levels (2.96 ± 2.11 and 1.77 ± 0.83 p \ 0.001, respectively) were higher than controls.
However, thyroid nodule frequency was similar in both groups [22 (30.1 %) vs. 12 (20 %)], also thyroid gland volume was not significantly different [9.23 ml (3.08–32.40) vs. 8.52 ml (4.28–50.29)] among groups. The percentages of patients with thyroid parenchymal heterogeneity, positive anti-thyroid peroxidase, anti-thyroglobulin, and AITD were similar. Cases were reclassified according to the presence of thyroid nodule in which similar HOMA-IR levels were detected (median 2.39 and 1.89, p = 0.093, respectively) despite the fact that the group with nodules had higher mean age (26.5 (18–37) vs. 21 (18–34), p = 0.013, respectively). Similar ratios of thyroid nodule and AITD were found in patients with PCOS and controls. Keywords Polycystic ovary syndrome Thyroid nodule Autoimmune thyroid disease
Introduction C. Duran (&) F. S. Burnik Division of Internal Medicine, Endocrinology and Metabolism, Konya Training and Research Hospital, 42100 Konya, Turkey e-mail: [email protected] M. Basaran Z. Kucukaydin Division of Obstetrics and Gynecology, Konya Training and Research Hospital, Konya, Turkey O. Kutlu U. Aslan S. Ecirli Division of Internal Medicine, Konya Training and Research Hospital, Konya, Turkey S. Bakdik Division of Radiology, Konya Training and Research Hospital, Konya, Turkey S. S. Erdem Department of Biochemistry, Konya Training and Research Hospital, Konya, Turkey
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women and its prevalence is reported as 5–10 % worldwide [1–3]. The characteristics of this syndrome are hirsutism, hyperandrogenism, menstrual disturbance, and infertility. Obesity, impaired glucose tolerance, and insulin resistance are wellknown features of this syndrome [1, 4, 5]. Nodular goiter and autoimmune thyroid disease (AITD) are also frequently seen endocrinological abnormalities [6]. Ultrasonography (USG) and autopsy series indicated a high prevalence of thyroid nodules (19–50 %) in general population [7, 8]. Although associated with well-known risk factors such as age, female gender, and iodine deficiency, exact pathogenesis remains obscure. Similar to nodular goiter, AITD is also frequently seen in reproductive women that may be due to the
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influence of hormonal and chromosomal factors in the etiology [9]. Previous studies reported a possible association between thyroid nodules and insulin resistance which is also proposed to be a risk factor for the development of cancer [10, 11]. To support this hypothesis, insulin-resistant conditions such as acromegaly [12], acrochordons [13], and metabolic syndrome [14], are known to be associated with increased risk of nodule development that also reversed with metformin treatment [15]. Insulin resistance and increased LH/FSH ratio are characteristic features of PCOS [16]. In addition to insulin resistance, the presence of increased LH/FSH ratio may also contribute to the development of goiter through the effect of increased LH on TSH receptors [16–18]. Despite the presence of opposing opinions [19, 20], majority of previous studies that were reported confirmed the coexistence for PCOS with nodular goiter and AITD [21–24]. In this study, we aimed to investigate goiter and AITD frequency in patients with PCOS.
Material and method This prospective study was conducted at Konya Training and Research Hospital, a tertiary care hospital, Clinics of Internal Medicine (Division of Endocrinology) and Obstetrics and Gynecology, between July 2013 and February 2014. Informed consent was taken from all participants. Study protocol was approved by Ethics Committee of Necmettin Erbakan University. Eighty-nine patients with PCOS ages between 18 and 40 were screened for the study and 73 of them enrolled in the study. Age-matched women without PCOS were used as controls. Diagnosis of PCOS was based on Rotterdam criteria with patients meeting at least two of three criteria; first, oligomenorrhea (cycles lasting longer than 35 days) or amenorrhea (less than 2 menstrual cycles in the past 6 months), second, clinical or biochemical hyperandrogenism, and third, polycystic appearance of ovary on USG and the exclusion of other causes of hyperandrogenism, such as Cushing’s syndrome, congenital adrenal hyperplasia, or virilization [15]. Subjects taking drugs in the last 6 months that may interfere with thyroid function tests (except from thyroid hormone and anti-thyroid drugs) or effecting on insulin resistance, such as estrogens, oral contraceptives, corticosteroids, immunosuppressants were excluded from the study. After enrollment, physical examination was performed and all data were recorded on patient forms. Height (m) and weight (kg) were measured with underwear clothing. Waist circumference was measured as the minimum size between iliac crest and lateral costal
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margin. Body mass index (BMI) was calculated as weight (kg) divided by height square (m2). Glucose, insulin, thyroid-stimulating hormone, free thyroxine, anti-thyroglobulin (anti-Tg), and anti-thyroid peroxidase (anti-TPO) autoantibodies were measured using fasting venous blood from the antecubital vein. Insulin resistance was calculated by homeostasis model assessment-insulin resistance (HOMA-IR) (fasting plasma glucose (mmol/l) 9 fasting serum insulin (lIU/ml)/22.5). All samples were taken after an overnight fasting and separated by centrifugation and stored in deep freezer at -70 °C until used for analysis. Fasting glucose levels (normal range (NR): 70–105 mg/ dl) were measured by Abbott C-16000 Autoanalyzer (Abbott Laboratories, Abbott Park, IL) with glucose oxidase method. Free T4 (NR 0.89–1.76 ng/dl), insulin (NR 3–25 mU/l), TSH (NR 0,35-5.5 lIU/ml) were measured by Advia Cetaur XP (Siemens Healthcare Diagnostics, Siemens AG, Germany) with chemiluminescence method; anti-thyroglobulin (anti-Tg) (NR 0–40 IU/ml) and anti-thyroid peroxidase (anti-TPO) (NR 0–40 IU/ml) autoantibodies were measured by Immulite 2000 (Siemens Healthcare Diagnostics, Siemens AG, Germany) with chemiluminescence method. Intra- and inter-assay CVs for TSH were 2.44 and 3.44, for free T4 were 1.77 and 2.9, and for insulin 4.6 and 5.9, respectively. Analytical sensitivity and intra-assay CV for anti-TPO were 5.0 IU/ml and 6.2, and for anti-Tg Ab 5.0 IU/ml and 5.9, respectively. Anti-TPO and anti-Tg autoantibodies concentration exceeding 40 IU/ml were considered positive. Thyroid USG examination was performed using the 5–13 MHz linear probe (Siemens Acuson Antares, Siemens AG, Germany). Assessment of the presence of nodules and parenchymal patterns were recorded on patients’ charts. All the USG nodular lesions measuring over 3 mm were considered as nodule. Thyroid volume was calculated by the elliptical shape volume formula (0.479 9 length 9 width 9 height) for each lobe and the sum of right and left thyroid lobe volume were calculated as total thyroid volume [10]. Statistical analysis Continuous variables were expressed as median (minimum–maximum) or mean ± standard deviation while categorical variables were presented as frequency and related percentage values. Mann–Whitney U test and independent samples t test were used for comparing groups. Chi-square test with Yates correction, Fisher’s exact test, and Fisher–Freeman–Halton test were used to compare categorical variables. Spearman’s correlation coefficient was used to analyze relationship between continuous variables and SPSS for Windows version 21 (IBM
Endocrine
Inc.) was used for recording and analysis of data. Statistical significance level was set at 0.05.
Results Clinical characteristics of patients are summarized in Table 1. In PCOS group, BMI values, (27.45 ± 5.73 and 22.55 ± 3.78 kg/m2, respectively, p \ 0.001), systolic [110 mmHg (90–130) vs. 100 mmHg (90–140), respectively, p = 0.016] and diastolic (72.67 ± 6.52 vs. 66.42 ± 8.88 mmHg, respectively, p \ 0.001) blood pressure, waist circumference (86.27 ± 14.41 vs. 78.78 ± 8.87 cm, respectively, p \ 0.001), and HOMA-IR Table 1 Sociodemographic and study parameters among groups PCOS group (n = 73)
Controls (n = 60)
p value
Age (year)
22 (18–37)
20.50 (19–35)
Height (m)
1.62 ± 0.06
1.63 ± 0.05
Weight (kg)
72.14 ± 16.39
59.67 ± 9.13
\0.001
Body Mass Index
27.45 ± 5.73
22.55 ± 3.78
\0.001
Systolic blood pressure (mmHg)
110 (90–130)
100 (90–140)
0.016
Diastolic blood pressure (mmHg) Waist circumference (cm)
72.67 ± 6.52
66.42 ± 8.88
\0.001
86.27 ± 14.41
78.78 ± 8.87
\0.001
Ferriman–Gallwey score
20 (8–32)
4.50 (1–8)
\0.001
Presence of oligoanovulation
63 (86.30)
0
\0.001
Ultrasonographic polycystic ovary appearances
58 (79.50)
0
\0.001
Glucose (mg/dl)
87.82 ± 10.84
82.08 ± 8.11
Insulin (lIU/ml)
13.42 ± 7.89
8.76 ± 4.01
\0.001 \0.001
0.785 0.356
0.001
HOMA-IR
2.96 ± 2.11
1.77 ± 0.83
TSH (lIU/ml)
2.09 (0.67–16.51)
1.96 (0.01–7.08)
0.397
Free T4 (ng/dl)
1.19 (0.73–1.84)
1.19 (0.81–1.99)
0.543
Anti-TPO positive patients
12 (16.40)
10 (16.70)
1.00
Anti-Tg positive patients
8 (11)
12 (20)
0.227
Anti-thyroid drug treatment
3 (4.10)
0
0.252
L-Thyroxine treatment Thyroid nodule
6 (8.20) 22 (30.10)
1 (1.70) 12 (20)
0.128 0.257
Heterogenous thyroid parenchyme
20 (27.40)
9 (15)
0.131
Total thyroid volume (ml)
9.23 (3.08–32.40)
8.52 (4.28–50.29)
0.539
Values were expressed as mean ± SD, mean (minimum–maximum), or n (%). HOMA-IR homeostasis model assessment-insulin resistance
levels (2.96 ± 2.11 vs. 1.77 ± 0.83 respectively, p \ 0.001) were higher than controls. Mean TSH, free thyroxine levels, the percentage of antiTPO [12/73 (16.4 %) and 10/60 (16.7 %), p = 1.0, respectively] and anti-Tg [8/73 (11 %) and 12/60 (20 %), p = 0.227, respectively] positive patients, and L-thyroxine or anti-thyroid drugs usage were similar in both groups (Table 1). The percentage of patients with thyroid parenchymal heterogeneity was similar in both groups [in PCOS group 20/73 (27.4 %) and in controls 9/60 (15 %), p = 0.131]. In PCOS and controls, thyroid nodule was detected in 22/73 (30.1 %) and 12/60 (20 %) patients (p = 0.26), respectively (Fig. 1). Thyroid gland volume was similar in both groups [in PCOS; median 9.23 ml (3.08–32.40) and, in controls; median 8.52 ml (4.28–50.29), p = 0.539, respectively]. In PCOS groups, 13 patients had single nodule and 9 patients had multiple nodules. In controls, 4 patients had single nodule and 8 patients had multiple nodules. If either thyroid heterogeneity and/or positivity of autoantibodies were considered as AITD, the frequency of AITD was found similar [in PCOS group; 23 (32.5 %) and in controls; 14 (23.3 %), p = 0.394] (Fig. 1). Cases were divided into with- or without thyroid nodule; in cases with thyroid nodule, median age were higher [26.5 (18–37) vs. 21 (18–34), p = 0.013, respectively] and similar HOMA levels were detected (median 2.39 (0.26–8.59) and 1.89 (0.47–14.08), p = 0.093, respectively, Table 2). Correlation analysis revealed a significant positive correlation between the age and the total thyroid volume (r = 0.28, p = 0.001), however, this correlation was not detected between HOMA-IR and thyroid volume (Table 3).
Fig. 1 Thyroid nodule and autoimmune thyroid disorders frequency in patients with- or without polycystic ovary syndrome
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Endocrine Table 2 Age and insulin resistance indices in patients with- or without thyroid nodule Presence of thyroid nodule Yes (n = 34) Age (year)
26.50 (18–37)
Glucose (mg/dl)
87 (71–119)
Insulin (lIU/ml) HOMA-IR
11.40 (1.42–35.50) 2.39 (0.26–8.59)
p value
No (n = 99) 21 (18–34)
0.013
85 (52–133)
0.349
9.29 (2.15–43.30) 1.89 (0.47–14.08)
0.147 0.093
Values are expressed as mean (minimum–maximum). HOMA-IR Homeostasis model assessment-insulin resistance Table 3 Correlation analysis between study parameters n = 133 Age HOMAIR
TSH r
0.02
p
0.805
r
0.08
p
0.351
Total thyroid volume 0.28 0.001 -0.02 0.867
r Spearman’s rank correlation coefficient, TSH thyroid-stimulating hormone, HOMA-IR homeostasis model assessment-insulin resistance
Discussion AITD, nodule frequency, and thyroid volume were similar in patients with- or without PCOS. Additionally, positive correlation was detected between age and thyroid volume. Ultrasonography and autopsy studies report the prevalence of thyroid nodule up to 50 % in elderly patients and in women, and its prevalence increases in iodine-deficient area [7, 8]. In Turkey, iodine prophylaxis was started in 1999 and our region is the mildly iodine-deficient area at the moment (average urinary iodine concentration, 92 lg/l) [25]. There are studies that indicated a relationship between insulin resistance and thyroid nodules in the last decade [10, 12–14, 20]. This causal relationship was confirmed because of reduction in thyroid nodule volume with amelioration of insulin resistance using metformin [15]. Insulin resistance and increased LH/FSH ratio are characteristic features of PCOS [16]. In this respect, we could expect an increased frequency of thyroid nodules in PCOS. However, paucity of studies about this subject is interesting to note. Moreover, current studies have significant methodological drawbacks to show any association. Although, Anaforoglu et al. failed to demonstrate an association between thyroid disorders and PCOS, subgroup analysis after reclassification according to metabolic syndrome revealed an association in PCOS group [20]. Increased antiTPO, anti-TG, thyroid volume, and heterogeneity in metabolic syndrome-associated PCOS patients, lead the authors to hypothesize that the association is related with the presence of metabolic syndrome rather than PCOS per se [20].
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Ayturk et al. also confirmed this hypothesis by demonstrating increased thyroid volume and frequency nodules in their metabolic syndrome patients [14]. Kauchei et al. reported increased goiter frequency in patients with PCOS. A significant limitation of this study is the use of manual examination for the diagnosis of goiter instead of USG which is considered as gold standard [19]. In our opinion, use of manual examination in the study potentially introduced significant bias in the detection of goiter. Despite an increased LH/FSH ratio (1.83 vs. 1.16) and HOMA-IR values (2.96 ± 2.11 vs. 1.77 ± 0.83), our results failed to demonstrate increased nodule frequency and thyroid volume. A lower level of HOMA-IR values compared with previous studies [10, 15] and/or association with metabolic syndrome instead of PCOS could explain this observation. Another important issue is AITD’s association with PCOS. Previous studies reported increased frequency of AITD with higher levels of autoantibodies. However, in the current study, we also failed to demonstrate a difference in anti-TPO and anti-Tg Ab levels among the groups. In a recent meta-analysis that included 6 studies [19–24], Danfeng et al. concluded that current evidence is directed toward and increased AITD frequency in PCOS [26]. Janssen et al. [21] and Sinha et al. [24] reported an increased AITD in PCOS patients. Janssen et al. speculated that hormonal influences (increased estrogen/progesteron levels) might be the cause [21]. Sinha et al. reported a antiTPO mean values of 28.037 ± 9.138 in controls and 25.72 ± 8.27 in PCOS group with a p value of 0.035. However, recalculation of p value with these data reveals a p value of 0.095 which is not significant [24]. On the other hand Ganie et al. [27] reported an increased PCOS frequency in AITD patients. But, we think that this study had significant selection bias in which they included only 13–18 years old girls. The mean age of menarche in their population was 12 years. Therefore, diagnosis of PCOS in this group of perimenarchial school girls was not only difficult but might be inappropriate. Additionally, considering the increasing anti-TPO titers with advancing age, AITD diagnosis in this population was expected to be significantly lower compared with adults. Ott et al., by taking a step further, claimed that anti-TPO titers could be used as a predictor for the success of ovulation induction in their PCOS patients treated for infertility [23]. In another study, published by Garelli et al., it was reported that patients with PCOS have higher AITD frequency than controls (27 vs. 8 %, respectively), but non-thyroid autoantiobodies (against parietal cells, intrinsic factor, adrenal-cortex, 21-hydroxilase, steroid producing cells, side-chain cleavage enzyme, islet-cell, glutamic acid decarboxylase, nuclei, and mitochondria) frequency were similar [22].
Endocrine
Kachuei et al. reported a higher anti-TPO titers in PCOS patients, despite a similar ratio of anti-TPO and anti-Tg positive patients in both groups. A significant drawback of this study is the lack of thyroid USG and antibody titers in some patients [19]. Despite the cumulated positive evidence about the association of AITD and PCOS, we failed to demonstrate this finding in our study groups. Despite an opinion about PCOS as an autoimmune disease [26], there is lack of uniformity in finding autoantibody titers and levels among those in previous studies that apparently included our findings. In our opinion, major drawback of our study might be the sample size, however considering the lack of the uniformity in diagnostic modalities exact calculation of sample sizes might not be possible with the current evidence. Therefore, studies with larger sample sizes with objective and standardized laboratory and imaging modalities were required before final comment on this subject.
Conclusion Our results failed to demonstrate a significant relation between thyroid volume, thyroid nodule, and AITD frequency in patients with- or without PCOS. The increased frequency of goiter and AITD in patient with PCOS may be related to component of metabolic syndrome rather than diagnosis of PCOS. Also suggested by previous studies, evaluation of thyroid nodules should be a part of evaluation of patients with PCOS specifically in cases with associated metabolic syndrome. Conflict of interest interest.
The authors declare that there is no conflict of
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