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Endocrine

, Volume 47, Issue 2, pp 512–518 | Cite as

Sustained high levels of serum leptin rather than IL-6 observed in patients with postpartum thyroiditis during their first postpartum year

  • Huiling Guo
  • Xiu Liu
  • Chenyang Li
  • Yushu Li
  • Miao Sang
  • Zhongyan Shan
  • Weiping TengEmail author
  • Haixia GuanEmail author
Original Article

Abstract

The purpose of the study is to explore the roles of leptin and interleukin-6 (IL-6) during the first postpartum year in the occurrence and development of postpartum thyroiditis (PPT). We retrospectively collected serum samples from 57 PPT patients consisting of 34 overt PPT (O-PPT) and 23 subclinical PPT (S-PPT) in addition to 37 healthy postpartum women at four postpartum time points, i.e., 3-day and 3, 6, 12-month postpartum. Serum leptin and IL-6 levels were measured by radioimmunoassay and ELISA assay, respectively. Leptin level and leptin/BMI (LEP/BMI) ratio were higher in PPT patients than in control during the first postpartum year, but were not significantly different between O-PPT and S-PPT. However, a similar trend but did not reach significant difference in IL-6 level was observed during the postpartum period in PPT patients and control women. We conclude that a sustained high level of serum leptin after delivery may be involved in the pathogenesis of PPT. IL-6 does not contribute to the development of PPT.

Keywords

Autoimmune Interleukin-6 Leptin Postpartum thyroiditis 

Introduction

Postpartum thyroiditis (PPT) is the occurrence of thyroid dysfunction in the first postpartum year in women who were euthyroid prior to pregnancy [1]. This is one of the most frequent autoimmune thyroid diseases (AITD) in women of childbearing age. In its classical form, transient thyrotoxicosis is followed by transient hypothyroidism with a return to the euthyroid state by the end of the initial postpartum year [2]. The prevalence of PPT varies globally from 1.1 to 21.1 % [3]. In our previous study, we noted that the prevalence in a Chinese cohort is 11.9 % [4].

A series of studies have revealed that the presence of thyroid peroxidase autoantibody (TPOAb), lymphocyte abnormalities, complement activation, increased levels of IgG1, increased natural killer cell activity, and specific human leukocyte antigen (HLA) haplotypes are correlated with the development of PPT [1, 5, 6]. The occurrence of PPT reflects the immune suppression that occurs during pregnancy which is followed by the rebound of the immune system in the postpartum period.

Leptin, a 16 kDa adipocyte-derived protein, was identified as a product of the obesity (ob) gene in which a recessive mutation results in food intake and energy expenditure defects [7]. Leptin is structurally classified as a member of the long-chain helical cytokine family, which also includes interleukin (IL) -6, IL-11, IL-12 or leukocyte inhibitory factor (LIF) [8]. Initially described as one of the anti-obesity hormones, leptin has subsequently been shown also to influence basal metabolism, hematopoiesis, thermogenesis, reproduction, angiogenesis and immune system responses [9]. Leptin is a pro-inflammatory adipokine which induces T helper 1 (Th-1) cells and may contribute to the development and progression of autoimmune responses [10]. In humans, the increase in leptin is associated with several autoimmune conditions, such as type 1 diabetes mellitus, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [11]. However, very few studies have specifically investigated the role of leptin in PPT.

IL-6 is a cytokine produced by various cells, including monocytes/macrophage, fibroblasts, thyrocytes, endothelial cells and several tumor cell lines [12]. An elevation in serum IL-6 level has been found in patients with several thyroid disorders, including subacute thyroiditis [13], amiodarone-induced thyrotoxicosis [14] and Graves’ disease [15, 16]. This prompted us to investigate whether this cytokine is involved in the development of PPT.

The aim of this study was to test the hypothesis that elevated levels of serum leptin and IL-6 may be related to the occurrence and development of PPT. With this objective in mind, we designed the present case–control study. By comparing the levels of serum leptin and IL-6 between PPT patients and healthy women at several time points throughout their first postpartum year, we evaluated the dynamic changes in the level of leptin and IL-6 and their potential link to the PPT development.

Subjects and methods

Subjects

The present study included 57 Chinese cases diagnosed with PPT and 37 healthy Chinese women as control. These subjects were all from our prevalence study of PPT described previously [4]. In that study, we screened PPT patients in a cohort consisting of 610 women who had normal thyroid function before delivery. PPT was defined as abnormal TSH occurring within 6 months postpartum without positive TSH receptor autoantibody (TRAb) and exophthalmos. Of the 57 patients, twenty-three showed TSH level abnormality and were classified as subclinical PPT (S-PPT), while the other 34 showed abnormalities in both TSH and thyroid hormones and were classified as overt PPT (O-PPT); Over all, seventy-nine percent of the patients (n = 45) had positive TPOAb and/or TgAb, while 12 (21 %) had negative thyroid autoantibodies [4].

The mean age and body mass index (BMI) of PPT patients (n = 57) were (25.72 ± 2.60) year and (25.03 ± 0.49) kg/m2, respectively, which were statistically comparable with those of healthy women [n = 37, mean age (26.62 ± 3.71) year, BMI (25.06 ± 0.42) kg/m2]. Patients with O-PPT were older than those with S-PPT [(26.63 ± 2.14) year vs. (24.30 ± 2.60) year, P = 0.005], but they were very similar in BMI levels [(25.02 ± 0.46) kg/m2 vs. (25.05 ± 0.55) kg/m2, P > 0.05].

Sampling

All venous blood samples were collected from patients in the morning (7:00–9:00 a.m.) after an overnight (at least 8 h) fast, at 3 days and 3, 6, 12-months after delivery. Blood samples were centrifuged shortly after sampling, and sera were separated and frozen in a serum bank at −70 °C until analysis.

Determination of thyroid profiles

The levels of serum TSH (detection limit, 0.002 mIU/L; reference range, 0.3–4.8 mIU/L), thyroid peroxidase autoantibody (TPOAb) (detection limit, 10 U/mL; cut-off level, 50 U/mL) and thyroglobulin autoantibody (TgAb) (detection limit, 20 U/mL; cut-off level, 40 U/mL) were determined in all participants within 5 days after sampling, using the automated immunochemiluminescent assay (ICMA) (DPC, USA) at a laboratory in our hospital. Free T3 (FT3) (reference range, 2.3–6.3 pmol/L), free T4 (FT4) (reference range, 10.3–24.5 pmol/L) and TSH receptor autoantibody (TRAb) (cut-off level, 2 IU/L) were detected subsequently if TSH was abnormal, using the ICMA assay (FT3 and FT4, DPC, USA) and a commercial ELISA kit (TRAb, Medipan Diagnostica Co., Germany), respectively. The intra- and inter-assay coefficient of variation for these serum parameters were <8 %.

Determination of leptin and IL-6 levels

Sera taken from the serum bank were measured for leptin and IL-6 concentrations. Serum leptin level was measured by radioimmunoassay using a Human Leptin Assay Kit (Cat.# HL-81 K) (Millipore, USA). The intra-assay and inter-assay coefficients of variation were 6.5 and 7.3 %, respectively. Serum IL-6 level was measured by an ELISA kit (Bender MedSystems, Austria). The intra-assay and inter-assay coefficients of variation were 7.7 and 9.1 %, respectively.

Statistical analysis

Numeric variables which adhered to a Gaussian distribution were presented as mean ± standard deviation (SD) and compared by Student’s t test and ANOVA test. For those data which did not adhere to a Gaussian distribution, descriptive statistics were therefore reported as median and range, and logarithmic (log) transformation was performed before applying the Mann–Whitney test for comparison. Finally, the relationship between variables was assessed using Spearman’s correlation coefficients. The level of significance was set at 5 %. Statistical analysis was done using SPSS software (version 13, Chicago, IL, USA).

Ethical aspects

Research protocols were approved by the Medical Ethics Committee of The First Affiliated Hospital of China Medical University. All subjects gave informed consent to participate in the study.

Results

Changes in thyroid profiles during the first postpartum year

In healthy women (control women), serum TSH levels were highest at 3-day postpartum (2.05 mIU/L) and declined thereafter (3-month, 6-month and 12-month vs. 3-day, P = 0.006, P = 0.000 and P = 0.003, respectively). In PPT patients, serum TSH concentrations were very similar as those in healthy women at 3-day after delivery, followed by a significant decline at 3-month postpartum (P = 0.000). TSH levels arose at 6-month (P = 0.019) and then decreased at 12-month postpartum to the levels at 3-day postpartum (P = 0.065). Significant differences in TSH levels between PPT patients and control were found at all time points investigated, except for 3-day postpartum (P = 0.062, P = 0.000, P = 0.000 and P = 0.006 at 3-day, 3-month, 6-month and 12-month postpartum, respectively) (Table 1; Fig. 1a).
Table 1

Thyroid function, leptin, LEP/BMI and IL-6 in participants during the first postpartum year

 

3 day pp

3 month pp

6 month pp

12 month pp

Control (n = 37)

PPT (n = 57)

Control (n = 37)

PPT (n = 57)

Control (n = 37)

PPT (n = 57)

Control (n = 37)

PPT (n = 57)

Leptin (μg/L)a

6.98 ± 0.27

8.60 ± 0.30**

7.34 ± 0.31

9.45 ± 0.38**

7.00 ± 0.35

8.45 ± 0.30**

6.94 ± 0.28

7.92 ± 0.34*

LEP/BMI (μg.m2/L.Kg)a

0.28 ± 0.01

0.34 ± 0.01**

0.29 ± 0.01

0.38 ± 0.01**

0.28 ± 0.01

0.34 ± 0.01**

0.28 ± 0.01

0.32 ± 0.01*

TSH (mIU/L)b

2.05

(0.47–4.68)

2.68

(0.71–9.71)

1.51##

(0.55–3.71)

0.24**##

(0.00–75)

1.17##

(0.32–4.73)

4.54**#

(0.00–75)

0.94##

(0.35–3.02)

2.25**

(0.02–16.7)

FT3 (pmol/L)a

N/A

4.09 ± 0.12

N/A

5.40 ± 0.30##

N/A

4.75 ± 0.23

N/A

5.10 ± 0.14#

FT4 (pmol/L)a

N/A

13.28 ± 0.43

N/A

23.93 ± 1.35##

N/A

15.90 ± 0.79#

N/A

17.41 ± 0.47##

IL-6 (pg/mL)b

9.76

(1.21–68)

15.31

(1.34–125.4)

1.35##

(0.1–15.86)

1.03##

(0.1–25.47)

0.54##

(0.33–2.66)

0.58##

(0.12–8.58)

0.13##

(0.02–0.58)

0.10##

(0.01–1.02)

N/A: did not test. PPT versus control: * P < 0.05, ** P < 0.01; 3 month pp, 6 month pp or 12 month pp versus 3 day pp: # P < 0.05, ## P < 0.01

PPT postpartum thyroiditis, pp postpartum, LEP/BMI leptin/body mass index

aMean ± SD

bMedian (minimum–maximum)

Fig. 1

Serum levels of TSH, leptin, LEP/BMI and IL-6 in healthy and PPT women. Serum TSH (a), leptin (b), ratio of leptin/BMI (c) and IL-6 (d) during the first postpartum (pp) year were compared between healthy women (control, n = 37) and patients with postpartum thyroiditis (PPT, n = 57). PPT versus control: *P < 0.05, **P < 0.01; 3 month pp, 6 month pp or 12 month pp versus 3 day pp: # P < 0.05, ## P < 0.01

In PPT patients, the FT4 concentration level fluctuated in the first postpartum year. The mean level of FT4 was lowest at 3-day postpartum. It significantly increased by 3-month postpartum (P = 0.000) and then decreased at 6- and 12-month postpartum, but remained higher than that at 3-day after delivery (P = 0.032 and P = 0.01, respectively). The mean levels of FT3 at 3- and 12-month postpartum were significantly increased compared with that at 3-day after delivery (P = 0.000 and P = 0.05, respectively) (Table 1).

Changes in leptin levels and LEP/BMI ratios during the first postpartum year

As shown in Table 1 and Fig. 1, serum leptin concentration did not change significantly with time during the first postpartum year in both control women and PPT patients. However, the level of leptin in sera was higher in PPT patients than in control women during the whole postpartum year (P = 0.000, P = 0.000, P = 0.003, P = 0.037 at 3-day, 3-month, 6-month and 12-month postpartum, respectively).

Since leptin concentration is affected by body mass, we calculated the ratio of LEP/BMI to correct this influence. We compared LEP/BMI ratios between PPT patients and controls, as well as ratios among different postpartum time points and observed that these ratios fluctuated in a manner similar to that of leptin concentration. (Table 1; Fig. 1b, c)

Changes in the level of IL-6 during the first postpartum year

It has been reported that a high level of IL-6 contributes to the pathogenesis of Graves’ disease. Thus, we asked whether this cytokine also plays a role in PPT. In controls, IL-6 concentration in sera was highest at 3-day postpartum and then quickly declined (all P = 0.000). The same fluctuation was observed in PPT. Results are presented in Table 1 and Fig. 1d. IL-6 level did not increase in PPT patients compared with controls at four time points in the first postpartum year.

Leptin, LEP/BMI and IL-6 levels in O-PPT and S-PPT

O-PPT and S-PPT were classified according to whether or not PPT patients exhibited an abnormal concentration of thyroid hormones, representing different severity of the disease. The trends in the change in serum leptin, LEP/BMI and IL-6 were similar between O-PPT and S-PPT patients. Although both level of leptin and LEP/BMI ratio in O-PPT patients were higher than those in S-PPT patients after delivery, the differences did not reach statistical significance. In addition, there were no significant differences in serum IL-6 concentrations between O-PPT and S-PPT patients at all time points investigated (Table 2).
Table 2

Serum leptin, LEP/BMI and IL-6 in O-PPT and S-PPT patients during the first postpartum year

 

3 day pp

3 month pp

6 month pp

12 month pp

O-PPT (n = 34)

S-PPT (n = 23)

O-PPT (n = 34)

S-PPT (n = 23)

O-PPT (n = 34)

S-PPT (n = 23)

O-PPT (n = 34)

S-PPT (n = 23)

Leptin (μg/L)a

9.11 ± 0.48

7.84 ± 0.43

9.97 ± 0.55

8.68 ± 0.42

8.49 ± 0.41

8.39 ± 0.43

8.23 ± 0.51

7.47 ± 0.42

LEP/BMI (μg m2/L Kg)a

0.36 ± 0.02

0.31 ± 0.01

0.40 ± 0.02

0.35 ± 0.02

0.34 ± 0.02

0.34 ± 0.01

0.33 ± 0.02

0.30 ± 0.01

IL-6 (pg/mL)b

13.2

(0.34–125.4)

16.2

(0.99–20.6)

0.88##

(0.1–25.47)

0.54##

(0.1–18.99)

0.57##

(0.12–8.58)

0.58##

(0.18–3.98)

0.10##

(0.01–1.02)

0.39##

(0.04–1.02)

O-PPT overt postpartum thyroiditis, S-PPT subclinical postpartum thyroiditis, pp postpartum, LEP/BMI leptin/body mass index

Three month pp, 6 month pp or 12 month pp versus 3 day pp: # P < 0.05, ## P < 0.01

aMean ± SD

bMedian (minimum–maximum)

Leptin and LEP/BMI levels in PPT with positive thyroid autoantibodies and PPT without autoantibodies

Patients were subgrouped into PPT with positive thyroid autoantibodies and PPT without positive autoantibodies. As shown in Fig. 2, serum leptin concentration and LEP/BMI ratio were not significantly different between the two subgroups at four postpartum time points.
Fig. 2

Serum level of leptin and LEP/BMI ratio in PPT women with and without autoantibodies. Serum leptin level (a) and leptin/BMI ratio (b) during the first postpartum (pp) year were compared between PPT patients with (w/antibodies, n = 45) and without (w/o antibodies, n = 12) positive TPOAb/TgAb

Correlation between thyroid function parameters and levels of leptin, LEP/BMI or IL-6

We pooled data from different time points to analyze the correlation between thyroid function parameters (TSH, FT4 and FT3) and levels of leptin, LEP/BMI or IL-6.

Serum TSH did not correlate with the levels of leptin, LEP/BMI or IL-6 in healthy women (P > 0.05). While in PPT patients, serum TSH concentration was negatively correlated with leptin level and with LEP/BMI ratios (r = −0.16, P = 0.018 and r = −0.17, P = 0.010, respectively). Serum FT4 concentration was positively correlated with leptin level and with LEP/BMI ratios (r = 0.14, P = 0.039 and r = 0.14, P = 0.040, respectively). Serum FT3 concentration also correlated with leptin level and with LEP/BMI ratios (r = 0.15, P = 0.022 and r = 0.16, P = 0.016, respectively). In PPT patients, TSH, FT4 and FT3 did not have any correlation with serum IL-6 concentration (P > 0.05).

Discussion

PPT is the occurrence of de novo autoimmune thyroid disease, excluding Graves’ disease, in the first postpartum year. Several years ago, we performed a prevalence study in an iodine-sufficient area in China and reported that PPT affected 11.9 % of women and generally was a transient condition [4]. In order to extensively understand the pathogenesis of this common disease, we began to investigate the relationship between immunological alteration and PPT. Previous studies attempted to explain the role of thyroid autoantibodies [4], IgG subtypes of TPOAb [17], as well as subsets of activated T cells and regulatory T cells [18] in the development of PPT. Results from these studies have indicated that an elevated titer of TPOAb favors the occurrence of PPT and that a dynamic IgG1 changes of TPOAb may be associated with thyroid damages. It has also been elucidated that a decrease in the number of CD4+ T cells and regulatory T cells, along with an increase in activated T cells, may be involved in the pathogenesis of PPT.

Given recent reports on the association of leptin and IL-6 with autoimmune status in Graves’ disease and Hashimoto thyroiditis [15, 19, 20, 21, 22], we speculated whether leptin and IL-6 levels show unusual fluctuations during the postpartum period that might be responsible for the occurrence of PPT. Therefore, in present study, we evaluated dynamic changes in the levels of serum leptin and IL-6 within the first postpartum year, using data from 57 PPT patients and 37 age- and BMI-matched healthy women. We found that in comparison with women in control group, PPT patients were shown to maintain higher levels of leptin during the first year postpartum. On the contrary, during the study period, IL-6 levels in sera were shown comparable dynamic changes between the PPT patients and control women.

Our result regarding the association between postpartum alteration in serum leptin and development of PPT is consistent with the available literature reported by Mazziotti et al. [23]. The latter study included sixty-one women who were positive for TPOAb (TPOAb+ve) and 20 women who were TPOAb-negative (−ve) in the first month postpartum. These women were monitored at 12, 16, 20 and 24 weeks’ postpartum. Throughout the study period, 32 of 61 TPOAb+ve women (52.4 %) developed PPT (PPTD group), whereas the remaining 29 TPOAb+ve women remained euthyroid (PPTE group). The authors found that at 4 weeks postpartum, TPOAb + ve women showed a higher serum leptin than TPOAb−ve women; PPTD patients maintained significantly higher leptin level and LEP/BMI ratio than healthy women; in PPTE women, however, a significant reduction in leptin level and LEP/BMI ratio was seen at 12 weeks’ postpartum. Taking the advantage of a larger sample size of PPT patients and a longer follow-up duration, results from present study provided additional data to give us a better understanding on the role of leptin in the etiology of PPT.

Some may question that the elevated leptin level was due to the alteration in TSH and thyroid hormone levels, as leptin signaling, which is mediated by the JAK/STAT pathway, is mandatory for maintenance of TRH expression in the paraventricular nucleus of hypothalamus and, consequently, for normal production of TSH and thyroid hormones [24]. However, the relationship between thyroid status and serum leptin remains controversial. Population studies have shown low, high and normal leptin levels in individuals with hypothyroidism [19, 20, 25, 26, 27, 28, 29]. Some studies reported that thyroid hormones could modulate serum leptin level [20, 26] while others did not find such correlation [25, 28, 29]. Moreover, although leptin and LEP/BMI ratio negatively correlated with TSH level and positively correlated with thyroid hormone level in PPT patients in our study, these parameters were maintained at a higher level than controls at the following time points: 3 days postpartum when PPT patients had comparable concentration of serum TSH and thyroid hormones; 3 months after delivery when PPT patients had significantly lower TSH and higher FT4; 6 months postpartum when PPT patients had significantly higher TSH. At the same time, the level of leptin was comparable between O-PPT and S-PPT, suggesting that it is not influenced significantly by the severity of PPT. Thus, we believe that the fluctuation in thyroid function alone cannot explain the elevation in leptin during the postpartum period in PPT.

However, how leptin contributes to the development of PPT remains unclear. It is worth noting that while pregnancy is an immune state dominated by Th-2 immune response, there is a rapid switch to a Th-1 status immediately postpartum when PPT occurs [30, 31]. As shown in some experimental studies, leptin acts as a stimulator of Th-1 immune responses in favoring the development of Th-1-mediated autoimmune disease, such as type 1 diabetes [32] and encephalomyelitis [33, 34]. Further research is needed to clarify the specific role of leptin in PPT.

In the present study, IL-6 level in serum peaked at 3-day postpartum and then rapidly declined in both healthy women and PPT patients. There was no correlation between serum IL-6 level and thyroid function profiles, suggesting that IL-6 may have no effect on the pathogenesis of PPT. Ahmad et al. came to the similar conclusion on the basis of two independent studies, New York Study and Cardiff Study [35]. Given that IL-6 is produced by B and T lymphocytes (mainly Th-2 cells), the significant decrease in level following delivery suggests that B and Th-2 cells are not major contributors to the occurrence of PPT. Furthermore, a low level of serum IL-6 in PPT may be of help to differentially diagnose PPT from postpartum Graves’ disease, because the latter condition is associated with an elevated level of IL-6 [15, 16, 36].

Besides the small sample size, there are some other limitations in our study. Firstly, leptin and IL-6 were measured in long-term frozen samples, which possibly affected the accuracy of the results. Secondly, we did not collect samples during pregnancy and peripartum stage; therefore, we were unable to determine when exactly the leptin level in sera started to be different in women who would develop PPT after delivery.

In conclusion, this study has demonstrated that leptin level was higher in women developing PPT than in healthy women. This suggests an involvement of leptin in the pathogenesis of PPT. Further studies are needed to clarify the specific contribution of leptin to PPT. IL-6 does not contribute to the development of PPT.

Notes

Acknowledgments

We are indebted to the postpartum women who participated in this study. We thank Renee Wang and LetPub Company for their linguistic assistance during the preparation of this manuscript. All the authors have nothing to declare. This study was supported by grants from the National Natural Science Foundation, Beijing, China (Grant #81170731).

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Huiling Guo
    • 1
  • Xiu Liu
    • 1
  • Chenyang Li
    • 2
  • Yushu Li
    • 1
  • Miao Sang
    • 1
  • Zhongyan Shan
    • 1
  • Weiping Teng
    • 1
    Email author
  • Haixia Guan
    • 1
    Email author
  1. 1.Department of Endocrinology and Metabolism, The First Affiliated Hospital of China Medical University; Institute of Endocrinology, The Liaoning Provincial Key Laboratory of Endocrine Diseases, China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Gynecology and ObstetricsShenyang Women’s and Children’s HospitalShenyangPeople’s Republic of China

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