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. 2025 Jun 6;25:140. doi: 10.1186/s12902-025-01943-y

Circulating leptin levels in thyroid dysfunction: a systematic review and meta-analysis

Shanshan Liu 1,3,4, Jun Ma 1,3,4, Leyuan Zhang 1,3,4, Yanlong Yang 1,3,4, Ziqi Han 3,4, Limin Tian 2,✉
PMCID: PMC12142830  PMID: 40481466

Abstract

Purpose

Leptin is an important regulator of energy homeostasis, analogous to thyroid hormone (TH). The purpose of this study was to investigate circulating leptin levels in thyroid dysfunction (TD) patients and the role of TH levels.

Methods

The electronic databases PubMed, Embase, Cochrane Library, and Web of Science were independently searched by two researchers, from inception until February 3, 2024, and updated on February 15, 2025. Pooled standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated by the random effects model.

Results

Thirty-eight studies reported circulating leptin levels in TD and control with euthyroidism, 4295 subjects were included in total, of which 1277 were hypothyroidism, 540 were hyperthyroidism, and 2478 were control. Compared to euthyroidism, leptin levels were significantly higher in hypothyroidism, and not significantly altered in hyperthyroidism (SMD [95%CI] = 0.71 [0.38, 1.04] and -0.03 [-0.57, 0.51], respectively). The subgroup analysis indicated that, compared to euthyroidism, leptin levels were significantly higher in subjects regardless of overt and subclinical hypothyroidism (SMD [95%CI] = 0.76 [0.25, 1.26] and 0.41 [0.11, 0.70], respectively), and not significantly different in overt hyperthyroidism (SMD [95%CI] = -0.14 [-0.74, 0.45]). Furthermore, when compared to age-, gender-, and body mass index (BMI)-matched euthyroidism, leptin levels were significantly higher in hypothyroidism and had no significant difference in hyperthyroidism (SMD [95%CI] = 0.66 [0.24, 1.07] and -0.43 [-1.13, 0.27], respectively). A total of 16 studies analyzed the correlations between leptin levels and TH levels in TD, 488 were hypothyroidism and 206 were hyperthyroidism. Following correlation analysis, leptin levels displayed a positive correlation with thyroid-stimulating hormone (TSH) levels (r = 0.19) and a negative correlation with triiodothyronine (T3) levels (r = -0.40) in TD.

Conclusion

Compared to euthyroidism, circulating leptin levels were significantly higher in hypothyroidism, and not significantly altered in hyperthyroidism. Besides, leptin levels in TD may be directly regulated by TSH and T3 levels, independent of BMI.

Trial registration

CRD42024561055.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12902-025-01943-y.

Keywords: Leptin, Thyroid dysfunction, Thyroid hormone, Meta-analysis

Introduction

Thyroid dysfunction (TD) is a common chronic endocrine disease, primarily including hypothyroidism and hyperthyroidism [1]. According to statistics, the prevalence of hypothyroidism and hyperthyroidism is about 0.25–4.2% and 0.1–1.25% worldwide, separately [2]. Depending on the etiology, TD is categorized into primary and secondary, which can be effectively differentiated following the location of the lesion and peripheral thyroid hormone (TH) levels. Primary TD is due to lesions of the thyroid gland itself, with elevated and decreased thyroid-stimulating hormone (TSH) levels in hypothyroidism and hyperthyroidism, respectively [3, 4]. Secondary TD is due to hypothalamic or pituitary pathology, with reduced or low normal TSH levels in secondary hypothyroidism and elevated or high normal TSH levels in secondary hyperthyroidism [5]. Besides, TD was categorized into clinical and subclinical forms according to whether free thyroxine (FT4) levels were abnormal [1]. TH is a key molecule in the regulation of metabolism and energy homeostasis [6, 7]. There are widespread systemic metabolic abnormalities and disturbances in energy balance in TD. Hypothyroidism typically presents with a decreased basal metabolic rate (BMR), fear of cold, loss of appetite, and weight gain, whereas in hyperthyroidism there is an increased BMR, fear of heat, excessive sweating, hyperphagia, and weight loss [8].

Leptin, a product of the obesity (ob) gene, produced and secreted by adipose tissue, maintains energy homeostasis by controlling appetite, energy expenditure, and fat metabolism primarily through binding to leptin receptors (ObRb) in the hypothalamus [9–11]. Leptin plays a key role in the negative feedback loop that regulates energy homeostasis. Circulating leptin levels increase during periods of increased body fat or high energy states, which suppresses appetite and accelerates metabolism; conversely, circulating leptin levels decrease during periods of decreased body fat or low energy states, triggering foraging behavior and reduced energy expenditure [10, 12]. Since its discovery, leptin has attracted considerable interest due to its wide range of physiological and pathological roles in various metabolic diseases [10]. Available evidence suggests that leptin maintains a complex dual relationship with the hypothalamic-pituitary-thyroid (HPT) axis [13]. However, whether leptin is involved in the pathogenesis of TD remains largely unknown. Several studies have explored leptin levels in primary TD, but no consensus has been achieved. Current studies have concluded that circulating leptin levels were elevated [14], decreased [15], or even unchanged [16] in hypothyroidism compared to euthyroid individuals. Similarly, compared to euthyroidism, circulating leptin levels in hyperthyroid patients were noted to be elevated by Dutta et al. [17], decreased by Oge et al. [14], and unchanged by Braclik et al. [16]. What's more, it has not been determined whether TH is directly involved in the regulation of leptin levels in TD [7]. Therefore, the present study aimed to investigate circulating leptin levels in TD patients and the role of TH levels.

Methods

The present study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards [18]. It has been registered in PROSPERO (https://www.crd.york.ac.uk/PROSPERO/), a platform for the International Prospective Register of Systematic Reviews, under the identifier CRD42024561055.

Search strategy

The electronic databases PubMed, Embase, Cochrane Library, and Web of Science were independently searched by two researchers, without language restrictions, from inception until February 3, 2024, and updated on February 15, 2025. The strategy for searching MeSH terms was as follows: (hypothyroidism OR hyperthyroidism OR thyroid diseases) AND (leptin). Additionally, we conducted a manual review of references from pertinent literature to prevent any exclusions. The detailed search strategy is demonstrated in Table S1.

Inclusion criteria and exclusion criteria

The TD patients were hypothyroid and hyperthyroid, respectively. Hypothyroidism was considered as serum TSH levels above the upper limit of the reference range with (overt hypothyroidism) or without (subclinical hypothyroidism) FT4 levels below the lower limit of the reference range. Hyperthyroidism is described as serum TSH levels below the lower limit of the reference range with (overt hyperthyroidism) or without (subclinical hyperthyroidism) FT4 levels above the upper limit of the reference range. Euthyroidism is defined as a healthy population without any thyroid disease, whose serum TSH and FT4 levels are within the reference range.

The criteria for inclusion entailed: (1) studies comparing circulating leptin levels in TD and controls with euthyroidism or analyzed the correlations between leptin levels and TH levels in TD; (2) leptin levels were presented as mean ± standard deviation (or can be calculated); (3) the study was made available in English.

The criteria for exclusion entailed: (1) reviews, conference abstracts, letters, editorial, commentary, case reports, and meta-analyses; (2) animal experiments; (3) taking medicine that affects thyroid function or body composition, such as levothyroxine, lithium; (4) the study conducted during pregnancy or lactation; (5) absence of data or complete texts.

In studies with more than one control group, we included those with characteristics more similar to the TD group for meta-analysis, prioritizing body mass index (BMI).

Data extraction and quality assessment

The literature was organized using EndNote 21 software. Two reviewers extracted data independently using a pre-designed form, and any disagreements were resolved by talking with the third reviewer. The first author, publication year, region, study type, thyroid state, sample size, gender, age, BMI, TSH, FT4, and detection method were among the details that were gathered and included in the data.

The quality assessment of prospective studies using the Newcastle–Ottawa Scale (NOS) [19] and cross-sectional studies using the Agency for Healthcare Research and Quality Scale (AHRQ) [20], of 0–3, 4–6, 7–9 stars in NOS and 0–3, 4–7, 8–11 in AHRQ scores represent the highest, medium, and lowest risk of bias, respectively. The above was implemented independently by two reviewers and any disagreements were resolved by a third reviewer.

Data synthesis and analysis

Meta-analyses were performed in STATA/MP 15. Standardized mean difference (SMD) with a 95% confidence interval (CI) to combine effect sizes for continuous variables. Effect size (ES) with a 95% CI to calculate the correlation coefficient (r). The chi-squared-based Q test and the I2 test assessed the size of heterogeneity. Studies with an I2 value of < 25%, 25%-75%, and > 75% were considered low, moderate, and high heterogeneity, respectively. A random effects model was selected to combine effect size, irrespective of heterogeneity. Subgroup analyses were performed following subtypes of TD (overt, subclinical, and mixed). Meta-regression analyses were conducted by characteristics of the TD patients (age, gender, BMI), detection method, sample type, study region, and publication date. Sensitivity analysis was conducted to determine the robustness of the pooled data by removing each study in turn. Additionally, we only included those studies that explicitly showed TD and euthyroidism were matched for age, gender, and BMI for sensitivity analysis. The funnel plot (the number of studies should be at least 10) and Egger's test were used to test publication bias. If publication bias existed, the trim-and-fill method was used to reconfirmation the stability of statistical results. Two-sided P values < 0.05 were considered statistically significant.

Result

Study search and inclusion

Figure 1 displays the screening process of the study. After excluding duplicate studies, titles and abstracts were filtered and 69 studies were obtained. By full-text review, 28 studies were eliminated for the following reasons: reviews (n = 1), letters (n = 1), conference abstracts (n = 7), with medicine (n = 1), no control (n = 5), no extractable data (n = 4), no full text (n = 9). Finally, 41 studies were included in the systematic review and meta-analysis.

Fig. 1.

Fig. 1

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Flow chart of study screening

Study characteristics and quality assessment

Table 1 presents the characteristics of the included studies reporting circulating leptin levels in TD and euthyroidism. Of these 38 studies, 4295 subjects were included in total, of which 1277 were hypothyroidism, 540 were hyperthyroidism, and 2478 were euthyroidism. Table 2 displays the characteristics of the included studies reporting the correlations between leptin levels and TH levels in TD. Among these 16 studies, 694 TD were included, of which 488 were hypothyroidism and 206 were hyperthyroidism. The study sites included Kyrgyzstan, Egypt, Iran, Iraq, India, Turkey, Japan, China, Kuwait, Bulgaria, Romania, Greece, Mexico, Brazil, Poland, Italy, Spain, Sweden, United Kingdom, Austria, Denmark, Germany, and America. The main methods of leptin detection included RIA and ELISA.

Table 1.

Characteristics of studies reporting circulating leptin levels in TD patients and euthyroidism

Study Region Study type Case Control Case–control match Measurement type (sample type)
State N (F/M) Age
(M ± SD) 		BMI
(M ± SD) 		TSH
(M ± SD) 		FT4
(M ± SD) 		N (F/M) Age
(M ± SD) 		BMI
(M ± SD) 		TSH
(M ± SD) 		FT4
(M ± SD)
Tomov et al. 2023 [21] Bulgaria Cross-sectional OHypo 40 (33/7) NA NA 9.66 ± 21.1 10.5 ± 3.4 21 (17/4) NA 21.6 ± 2.8 NA NA NA ELISA (serum)
OHyper 5 (2/3) 0.51 ± 0.9 17.1 ± 9.8
Stoica et al. 2022 [22] Romania Cross-sectional SHypo 11 (11/0) NA 33.75 ± 4.53 5.99 ± 3.71 1.14 ± 0.1 14 (14/0) NA 31.91 ± 5.92 2.08 ± 1.32 1.13 ± 0.26 Gender, BMI IF (serum)
El Amrousy et al. 2022 [23] Egypt Cross-sectional OHypo 30 (19/11) 11 ± 2.17 20.2 ± 4.1 22.4 ± 7.1 8.7 ± 1.1 30 (18/12) 10.8 ± 2.13 19.9 ± 2.2 2. 8 ± 0.67 18 ± 3.5 Age, gender, BMI ELISA (serum)
Keikhaei et al. 2021 [24] Iran Prospective OHypo 56 35.29 ± 10.65 23.9 ± 3.61 79.65 ± 21.24 0.45 ± 0.16 54 36 ± 8.64 22.79 ± 4.04 1.58 ± 0.82 1.27 ± 0.19 Age, gender, BMI ELISA (serum)
OHyper 54 36.22 ± 8.77 22.75 ± 4.14 0.02 ± 0.01 3.12 ± 0.75
Hammo et al. 2020 [25] Iraq Cross-sectional OHypo 35 (0/35) NA NA 26.36 ± 1.712 NA 20 (0/20) NA NA 2.230 ± 0.107 NA Age, gender ELISA (serum)
OHyper 35 (0/35) 0.049 ± 0.019 NA
Stratigou et al. 2018 [26] Greece Prospective SHypo 120 (72/48) 47.2 ± 16.4 25.6 ± 3.6 8.6 ± 1.7 1.3 ± 0.4 120 (72/48) 47.4 ± 15.1 24.4 ± 3.1 2.6 ± 0.6 1.5 ± 0.3 Age, gender ELISA (serum)
El-Zawawy et al. 2018 [27] Egypt Cross-sectional Hypo 120 (0/120) 41.40 ± 11.91 NA NA NA 120 (0/120) 40.15 ± 12.21 NA NA NA Age, gender ELISA (serum)
Lozanov et al. 2017 [28] Bulgaria Cross-sectional OHypo 59 (40/19) NA NA 19.67 ± 23.34 10.72 ± 2.46 59 (35/24) NA NA 1.79 ± 0.91 13.26 ± 1.71 NA ELISA (serum)
Kar et al. 2017 [29] India Cross-sectional Hypo 40 (24/16) NA NA 10.37 ± 4.10 NA 40 NA NA 2.41 ± 2.09 NA Age, gender ELISA (serum)
Gómez-Zamudio et al. 2016 [30] Mexico Cross-sectional Hypo 49 44.1 ± 11.6 47.9 ± 7.8 4.78(2.34–7.4)* 1.22(1.09–1.5)* 49 44.4 ± 12.0 46.2 ± 9.1 2.69 (2.05–3.5)* 1.24 (1.17–1.4)* Age, BMI ELISA (serum)
Akbaba et al. 2015 [31] Turkey Prospective SHypo 51 (41/10) 36.9 ± 10.6 26.1 ± 5.5 6.2 ± 1.3 0.8 ± 0.1 43 (32/11) 34.9 ± 8.4 25.7 ± 4.2 1.9 ± 0.8 1.02 ± 0.2 Age, gender, BMI ELISA (serum)
Tohma et al. 2015 [32] Turkey Prospective OHyper 21 (16/5) 39.6 ± 11.6 25 ± 4.4 0.01 (0–0.02)& 1.9 (0.8–4.64)& 33 (25/8) 36.4 ± 14.4 25 ± 4.3 1.24 (0.47–2.46)& 1.16 (0.93–1.45)& Age, gender, BMI ELISA (serum)
Yildiz et al. 2013 [33] Turkey Cross-sectional Hypo 27 (23/4) 43.3 ± 12.8 27.2 ± 4.4 33.2 ± 29.2 0.81 ± 0.3 31 (24/7) 40.3 ± 10.6 25.4 ± 5.1 1.94 ± 0.78 1.10 ± 0.92 Age, gender, BMI ELISA (serum)
Hyper 27 (18/9) 43.1 ± 14.9 25.8 ± 4.2 0.194 ± 0.2 2.01 ± 1.55
Yildiz et al. 2013 [34] Turkey Prospective SHypo 43 (43/0) 33.4 ± 10.3 25.3 ± 5.1 9.17 ± 6.44 13.67 ± 1.75 53 (53/0) 34.1 ± 8.2 26.6 ± 5.9 1.91 ± 0.94 15.35 ± 1.85 Age, gender, BMI RIA (serum)
Guzel et al. 2013 [35] Turkey Cross-sectional OHypo 40 (40/0) 39.83 ± 5.62 26.56 ± 1.36 56.3 ± 27.8 6.1 ± 3.3 25 (25/0) 39.16 ± 5.57 26.11 ± 1.59 2.6 ± 0.9 16.2 ± 2.4 Age, gender, BMI ELISA (serum)
SHypo 25 (25/0) 40.56 ± 4.90 26.48 ± 1.29 11.9 ± 3.3 14.6 ± 2.5
Dutta et al. 2012 [17] India Prospective OHyper 27 (16/11) 31.3 ± 2.2 20.5 ± 0.7 0.1 ± 0.0 NA 28 (14/14) 30.0 ± 1.8 21.6 ± 0.6 NA NA Age, BMI ELISA (plasma)
Teixeira et al. 2009 [36] Brazil Prospective OHypo 20 (20/0) 43.5 ± 15.0 27.1 ± 4.8 57.7 ± 49.4 0.5 ± 0.3 28 (28/0) 45.7 ± 9.9 26.3 ± 6.9 1.5 ± 0.7 1.31 ± 0.2 Age, gender, BMI RIA (serum)
SHypo 55 (55/0) 46.1 ± 11.1 27.1 ± 4.8 7.4 ± 2.6 1.0 ± 0.2
Guldiken et al. 2008 [37] Turkey Cross-sectional OHypo 25 (18/7) 41.4 ± 8.2 28.6 ± 5.8 44.6 ± 25.2 0.63 ± 0.22 25 (20/5) 36.8 ± 5.6 28.1 ± 6.8 1.3 ± 0.6 1.32 ± 0.19 Age, gender, BMI ELISA (serum)
SHypo 30 (28/2) 39.7 ± 10.5 27.3 ± 4.8 8.5 ± 1.9 1.21 ± 0.23
Braclik et al. 2008 [16] Poland Prospective OHypo 11 (11/0) 42.83 ± 10.09 25.55 ± 3.76 151.6 (23.3–913.7) & 4.7 (2.6–10.6) & 19 (19/0) 36.54 ± 10.83 23.56 ± 3.07 1.52 (0.5–11.4) & 14.5 (11.1–18.1) & Age, gender, BMI EIA (serum)
OHyper 17 (17/0) 41.78 ± 12.68 23.95 ± 3.93 0.097 (0.05–0.3) & 52.9 (35.9–126.3) &
Oge et al. 2005 [14] Turkey Prospective OHypo 26 (14/12) 40.8 ± 10.4 24.35 ± 3.83 22.2 ± 7.6 0.9 ± 0.5 20 (10/10) 35 ± 8.5 23.7 ± 5.7 2.08 ± 2.3 1.4 ± 0.8 Age, gender, BMI RIA (serum)
OHyper 22 (12/10) 44 ± 13.6 22.45 ± 4.86 0.01 ± 0.2 6.3 ± 1.5
Santini et al. 2004 [38] Italy Cross-sectional OHypo 15 (11/4) 38.7 ± 11.4 25.6 ± 4.1 53.8 ± 18.1 0.7 ± 0.1 15 (11/4) 40.5 ± 12.2 25.2 ± 4.7 1.42 ± 0.6 13.9 ± 2.6 Age, gender, BMI RIA (serum)
OHyper 15 (11/4) 39.5 ± 12.4 25.0 ± 4.4 0.01 ± 0.01 44.8 ± 19.7
Iglesias et al. 2003 [39] Spain Prospective OHypo 20 (17/3) 51.5 ± 4.1 28.5 ± 1.0 62.6 ± 9.0 5.6 ± 0.5 20 (17/3) 43.1 ± 2.6 25.1 ± 0.9 1.8 ± 0.3 14.8 ± 0.6 Age, gender RIA (serum)
OHyper 20 (16/4) 47.2 ± 3.9 22.7 ± 0.5 0.05 ± 0.004 45.8 ± 3.1 Age, gender, BMI
Wahrenberg et al. 2002 [40] Sweden Prospective Hyper 10 (10/0) 38 ± 4 24.0 ± 1.6  < 0.03 NA 16 (16/0) 34 ± 1 23.7 ± 0.5 2.00 ± 0.25 NA Age, gender, BMI RIA (serum)
Hsieh et al. 2002 [41] China Prospective OHypo 33 (26/7) 41.0 ± 10.4 23.7 ± 2.5 46.5 ± 4.6 2.6 ± 1.3 38 (30/8) 40.2 ± 11.3 23.1 ± 2.5 1.6 ± 0.5 19.9 ± 5.1 Age, gender RIA (serum)
Tagliaferri et al. 2001 [42] United Kingdom Cross-sectional SHypo 108 (92/16) 46.8 ± 15.7 43.4 ± 6.6 6.4 ± 2.7 11.8 ± 2.4 131 (100/31) 47.8 ± 14.0 42.9 ± 6.8 2.1 ± 1.1 12.3 ± 2.2 Age, gender, BMI RIA (serum)
Obermayer-Pietsch et al. 2001 [43] Austria Prospective OHyper 28 (23/5) 66 ± 8 23.5 ± 3.3 0.02 ± 0.03 36.5 ± 21.8 24 (22/2) 63 ± 12 23.9 ± 2 1.1 ± 0.9 16.5 ± 2 Age, gender, BMI RIA (plasma)
Nakamura et al. 2000 [44] Japan Prospective OHyper 32 (32/0) 41 ± 3 19.9 ± 0.4  < 0.02 77.3 ± 9.6 30 (30/0) 48 ± 3 20.6 ± 0.5 NA 14.9 ± 0.5 Age, gender, BMI RIA (serum)
Matsubara et al. 2000 [45] Japan Prospective OHypo 19 (19/0) 54.41 ± 16.89 24.6 ± 3.9 NA NA 197 (197/0) 52.10 ± 13.05 23.5 ± 4.0 NA NA Age, gender RIA (serum)
OHyper 27 (27/0) 43.18 ± 12.34 19.7 ± 3.1 NA NA
Chen et al. 2000 [46] China Cross-sectional OHypo 20 (20/0) 42.1 ± 3.7 24.2 ± 0.6 23.47 ± 4.50 7.7 ± 1.3 20 (20/0) 41.7 ± 2.4 21.0 ± 0.5 1.06 ± 0.14 14.2 ± 1.3 Age, gender RIA (plasma)
OHyper 20 (20/0) 39.6 ± 2.6 20.9 ± 0.6 0.01 ± 0.01 37.4 ± 3.9 Age, gender, BMI
Al-Shoumer et al. 2000 [47] Kuwait Prospective OHyper 19 (19/0) 34 ± 2 22.8 ± 0.9  < 0.01 85.3 ± 8.4 20 (20/0) 31 ± 2 24.2 ± 0.9 1.30 ± 0.2 15.9 ± 0.6 Age, gender, BMI RIA (serum)
OHyper 10 (0/10) 34 ± 2 22.2 ± 1.6  < 0.01 86.8 ± 8.1 12 (0/12) 35 ± 3 25.0 ± 1.0 1.10 ± 0.3 16.2 ± 0.8
Kautzky-Willer et al. 1999 [48] Austria Prospective OHypo 12 (10/2) 51.1 ± 4.9 22.5 ± 0.7 24.4 ± 4.6 NA 22 (20/2) 42.3 ± 6.8 22.9 ± 1.9 1.36 ± 0.2 NA Age, gender, BMI RIA (plasma)
OHyper 10 (8/2) 44.4 + 6.0 21.8 ± 0.7  < 0.1 NA
OHypo 13 (11/2) 56.0 ± 4.1 32.2 ± 1.4 23.7 ± 3.5 NA 22 (20/2) 45.8 ± 7.5 31.5 ± 4.7 2.3 ± 0.5 NA Age, gender, BMI
OHyper 9 (8/1) 52.1 ± 5.2 28.5 ± 1.3  < 0.1 NA
Zimmermann-Belsing et al. 1998 [49] Denmark Prospective OHyper 10(8/2) 50 24 0.01 ± 1.2 NA 18 (12/6) 39 24 NA NA Age, gender, BMI RIA (serum)
Yoshida et al. 1998 [15] Japan Cross-sectional OHypo 17 (17/0) 44.4 ± 3.4 22.3 ± 0.7 108.3 ± 27.7 4.9 ± 0.5 23 (23/0) 36.8 ± 3.1 21.6 ± 0.5 1.9 ± 0.2 14.9 ± 0.5 Age, gender, BMI RIA (serum)
OHyper 19 (19/0) 34.9 ± 2.4 20.7 ± 0.4  < 0.02 77.7 ± 5.7
Pinkney et al. 1998 [50] United Kingdom Prospective OHypo 22 (20/2) 48.74 ± 17.83 26.10 ± 4.63 43 (31.5–50) & NA 32 (19/13) 42.67 ± 17.05 24.02 ± 3.27 1.2 (0.78–2.53) * NA Age RIA (plasma)
OHyper 18 (17/1) 42.78 ± 14.08 23.0 ± 2.48  < 0.05 NA
Ozata et al. 1998 [51] Turkey Prospective OHypo 20 (20/0) 24.05 ± 5.2 23.1 ± 1.78 164.6 ± 17.9 0.47 ± 0.25 20 (20/0) 22.9 ± 4.15 22.8 ± 1.32 1.58 ± 0.50 1.43 ± 0.32 Age, gender, BMI RIA (plasma)
Hyper 20 (20/0) 25.5 ± 7.2 22.2 ± 3.1 0.024 ± 0.03 5.5 ± 3.7
Leonhardt et al. 1998 [52] Germany Cross-sectional OHypo 23 (19/4) 51.2 ± 2.8 26.8 ± 1.0 69.35 ± 9.66 0.04 ± 0.03 21 (13/8) 51.7 ± 3.6 23.8 ± 1.1 1.13 ± 0.13 0.12 ± 0.01 NA RIA (serum)
OHyper 19 (14/5) 55.8 ± 3.8 23.9 ± 0.9 0.01 ± 0.00 0.49 ± 0.01
Sreenan et al. 1997 [53] America Cross-sectional OHypo 6 (3/3) 62.2 ± 5.3 30.1 ± 0.7 72.8 ± 16.1 NA 11 (8/3) 55.0 ± 5.9 27.2 ± 2.5 1.2 ± 0.2 NA Age, gender, BMI RIA (serum)
OHyper 6 (6/0) 40.3 ± 7.2 28.0 ± 1.2 0.04 ± 0.003 NA
Corbetta et al. 1997 [54] Italy Prospective OHypo 25 (25/0) NA 25 ± 6.3 54.6 ± 12.6 4.4 ± 2.8 561 (561/0) NA 24.4 ± 4 0.3 ± 4.0 10 ± 18 Gender, BMI RIA (serum)
OHyper 27 (27/0) NA 22.6 ± 3.5  < 0.01 36.3 ± 19.8
OHypo 11 (0/11) NA 26 ± 6 22.8 ± 17.8 7.6 ± 3.6 393 (0/393) NA 24.6 ± 3.3
OHyper 13 (0/13) NA 26.2 ± 5.9  < 0.01 34.2 ± 14.3
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Hypo hypothyroidism, OHypo overt hypothyroidism, SHypo subclinical hypothyroidism, Hyper hyperthyroidism, OHyper overt hyperthyroidism, N sample size, F females, M males, BMI body mass index, TSH thyroid-stimulating hormone, FT4 free thyroxin, RIA radioimmunoassay, ELISA enzyme-linked immunosorbent assay, IF immunofluorescence, EIA immunoenzymatic assays, NA unknown. * median (p25-p75); & median (minimum–maximum)

Table 2.

Characteristics of studies reporting correlations between leptin levels and TH levels in TD

Study Region Study type Case Detection method (sample type)
State N (F/M) Age (M ± SD) BMI (M ± SD) TSH FT4
El Amrousy et al. 2022 [23] Egypt Cross-sectional Hypothyroidism 30 (19/11) 11 ± 2.17 20.2 ± 4.1 22.4 ± 7.1 8. 7 ± 1.1 ELISA (serum)
Hypothyroidism 30 (20/10) 10.6 ± 2.1 30 ± 4.3 26.2 ± 9.6 8.1 ± 1.7
Keikhaei et al. 2021 [24] Iran Prospective Hypothyroidism 56 35.29 ± 10.65 23.9 ± 3.61 79.65 ± 21.24 0.45 ± 0.16 ELISA (serum)
Hammo et al. 2020 [25] Iraq Cross-sectional Hypothyroidism 35 (0/35) NA NA 26.36 ± 1.712 NA ELISA (serum)
Hyperthyroidism 35 (0/35) NA NA 0.049 ± 0.019 NA
Lozanov et al. 2017 [28] Bulgaria Cross-sectional Hypothyroidism 59 (40/19) NA NA 19.67 ± 23.34 10.72 ± 2.46 ELISA (serum)
Akbaba et al. 2015 [31] Turkey Prospective Hypothyroidism 51 (41/10) 36.9 ± 10.6 26.1 ± 5.5 6.2 ± 1.3 0.8 ± 0.1 ELISA (serum)
Ağbaht et al. 2014 [55] Turkey Prospective Hyperthyroidism 40 (22/18) 49.5 ± 15.2 26.2 ± 4.5 0.01 (0.005–0.03)* 29.2 (21.0–42.8) * RIA (plasma)
Guzel et al. 2013 [35] Turkey Cross-sectional Hypothyroidism 40 (40/0) 39.83 ± 5.62 26.56 ± 1.36 56.3 ± 27.8 6.1 ± 3.3 ELISA (serum)
Saraç et al. 2010 [56] Turkey Prospective Hypothyroidism 30 (30/0) 39.9 ± 4.1 23.2 ± 2.5 8.7 ± 2.6 0.75 ± 0.1 ELISA (serum)
Teixeira et al. 2009 [36] Brazil Prospective Hypothyroidism 20 (20/0) 43.5 ± 15.0 27.1 ± 4.8 57.7 ± 49.4 0.5 ± 0.3 RIA (serum)
Hypothyroidism 55 (55/0) 46.1 ± 11.1 27.1 ± 4.8 7.4 ± 2.6 1.0 ± 0.2
Braclik et al. 2008 [16] Poland Prospective Hypothyroidism 11 (11/0) 42.83 ± 10.09 25.55 ± 3.76 151.6 (23.3–913.7) & 4.7 (2.6–10.6)& EIA (serum)
Hyperthyroidism 17 (17/0) 41.78 ± 12.68 23.95 ± 3.93 0.097 (0.05–0.3) & 52.9 (35.9–126.3)&
Oge et al. 2005 [14] Turkey Prospective Hypothyroidism 26 (14/12) 40.8 ± 10.4 24.35 ± 3.83 22.2 ± 7.6 0.9 ± 0.5 RIA (serum)
Hyperthyroidism 22 (12/10) 44 ± 13.6 22.45 ± 4.86 0.01 ± 0.2 6.3 ± 1.5
Yaturu et al. 2004 [57] America Prospective Hyperthyroidism 35 NA NA NA NA EIA (serum)
Al-Shoumer et al. 2000 [47] Kuwait Prospective Hyperthyroidism 29 (19/10) 34 ± 2 23.0 ± 0.9  < 0.01 85.6 ± 6 .0 RIA (serum)
Zimmermann-Belsing et al. 1998 [49] Denmark Prospective Hyperthyroidism 10(8/2) 50 24 0.01 ± 1.2 NA RIA (serum)
Pinkney et al. 1998 [50] United Kingdom Prospective Hypothyroidism 22 (20/2) 48.74 ± 17.83 26.10 ± 4.63 43 (31.5–50)& NA RIA (plasma)
Hyperthyroidism 18 (17/1) 42.78 ± 14.08 23.0 ± 2.48  < 0.05 NA
Leonhardt et al. 1998 [52] Germany Cross-sectional Hypothyroidism 23 (19/4) 51.2 ± 2.8 26.8 ± 1.0 69.35 ± 9.66 0.04 ± 0.03 RIA (serum)
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N sample size, F females, M males, BMI body mass index, TSH thyroid-stimulating hormone, FT4 free thyroxin, RIA radioimmunoassay, ELISA enzyme-linked immunosorbent assay, EIA immunoenzymatic assays, NA unknown. * median (p25-p75); & median (minimum–maximum)

The results of quality assessment by NOS for prospective studies showed a minimum of 6 stars and a maximum of 9 stars (Table S3), and AHRQ for cross-sectional studies showed a minimum quality score of 5 and a maximum quality score of 8 (Table S4). Overall, the included studies were of medium to high quality.

Meta-analysis

Comparison of circulating leptin levels in hypothyroidism than in euthyroidism

Thirty-six studies analyzed circulating leptin levels in hypothyroidism and euthyroidism. The pooled result demonstrated that leptin levels were significantly higher in hypothyroidism than in euthyroidism (SMD [95%CI] = 0.71 [0.38, 1.04], I2 = 93.30%, P = 0.000, Fig. 2). Furthermore, the subgroup analysis indicated that leptin levels were significantly higher in subjects regardless of overt (SMD [95%CI] = 0.76 [0.25, 1.26], I2 = 93.90%, P = 0.003, Fig. 2) and subclinical (SMD [95%CI] = 0.41 [0.11, 0.70], I2 = 75.10%, P = 0.006, Fig. 2) hypothyroidism than in euthyroid subjects.

Fig. 2.

Fig. 2

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Forest plot of circulating leptin levels in hypothyroidism and euthyroidism. OHypo, overt hypothyroidism; SHypo, subclinical hypothyroidism; Hypo, hypothyroidism; SMD, standardized mean difference; CI, confidence interval

In the sensitivity analysis, when compared to age-, gender-, and BMI-matched euthyroidism, leptin levels were significantly higher in hypothyroidism (SMD [95%CI] = 0.66 [0.24, 1.07], I2 = 91.30%, P = 0.002, Fig. 3).

Fig. 3.

Fig. 3

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Forest plot of circulating leptin levels in hypothyroidism and age-, gender-, and BMI-matched euthyroidism. SMD, standardized mean difference; CI, confidence interval

Comparison of circulating leptin levels in hyperthyroidism than in euthyroidism

Twenty-seven studies analyzed circulating leptin levels in hyperthyroidism and euthyroidism. The pooled result indicated that leptin levels in hyperthyroidism were not significantly different from euthyroidism (SMD [95%CI] = -0.03 [-0.57, 0.51], I2 = 94.40%, P = 0.904, Fig. 4). Furthermore, the subgroup analysis indicated that leptin levels had no significant difference in subjects with overt hyperthyroidism than in euthyroid subjects (SMD [95%CI] = -0.14 [-0.74, 0.45], I2 = 94.70%, P = 0.631, Fig. 4).

Fig. 4.

Fig. 4

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Forest plot of circulating leptin levels in hyperthyroidism and euthyroidism. OHyper, overt hyperthyroidism; Hyper, hyperthyroidism; SMD, standardized mean difference; CI, confidence interval

In the sensitivity analysis, when compared to age-, gender-, and BMI-matched euthyroidism, leptin levels had no significant difference in hyperthyroidism (SMD [95%CI] = -0.43 [-1.13, 0.27], I2 = 94.50%, P = 0.230, Fig. 5).

Fig. 5.

Fig. 5

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Forest plot of circulating leptin levels in hyperthyroidism and age-, gender-, and BMI-matched euthyroidism. SMD, standardized mean difference; CI, confidence interval

Correlations between leptin levels and TH levels in TD

Sixteen studies demonstrated the correlations between leptin levels and TH levels, including TSH, thyroxine (T4), triiodothyronine (T3), FT4, and free triiodothyronine (FT3). As shown in Table 3, leptin levels displayed a positive correlation with TSH levels (r = 0.19, P = 0.015) and a negative correlation with T3 levels (r = -0.40, P = 0.010) in TD.

Table 3.

Correlations between leptin levels and TH levels in TD

Parameters N r [95%CI] I2 (%) P-value
TSH 527 0.19 [0.04, 0.34] 66.70 0.015
T4 70 -0.46 [-0.88, 0.35] 92.00 0.255
T3 144 -0.40 [-0.64, -0.10] 70.00 0.010
FT4 286 -0.08 [-0.26, 0.11] 56.40 0.397
FT3 286 0.05 [-0.17, 0.26] 67.60 0.664
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TSH thyroid-stimulating hormone, T4 thyroxine, T3 triiodothyronine, FT4 free thyroxine, FT3 free triiodothyronine, N sample size, r correlation coefficient, CI confidence interval

Meta-regression analysis

As presented in Table 4, meta-regression analyses were conducted by age, gender, BMI, detection method, sample type, study region, and publication date indicating that these factors were not a source of heterogeneity among studies (P > 0.05).

Table 4.

Meta-regression analysis of studies reporting circulating leptin levels in TD and euthyroidism

Covariates Hypothyroidism and Euthyroidism Hyperthyroidism and Euthyroidism
Coefficient [95% CI] P-value Coefficient [95% CI] P-value
Age (years) -0.01 [-0.05, 0.03] 0.666 -0.02 [-0.11, 0.07] 0.653
Gender 0.20 [-0.63, 1.04] 0.619 -0.02 [-1.88, 1.85] 0.986
BMI (kg/m2) -0.01 [-0.06, 0.05] 0.856 -0.01 [-0.21, 0.20] 0.956
Detection method -0.47 [-1.37, 0.43] 0.296 -1.08 [-4.29, 2.13] 0.489
Sample type 1.28 [-0.34, 2.89] 0.117 2.41 [-0.02, 4.84] 0.051
Study region 0.09 [-0.20, 0.37] 0.549 0.10 [-0.30, 0.50] 0.608
Publication date 0.08 [-0.07, 0.23] 0.297 0.01 [-0.31, 0.33] 0.930
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BMI body mass index, CI confidence interval

Sensitivity analysis and publication bias

Sensitivity analyses showed that the pooled results remained unchanged before and after excluding each study in turn, indicating relatively stable (Figure S1). The funnel plot and Egger's test showed that publication bias was absent (Figure S2 and Table S2).

Discussion

The present study found that circulating leptin levels were significantly higher in hypothyroidism, and not significantly altered in hyperthyroidism compared to euthyroidism; the above associations remained after adjusting for age, gender, and BMI. What's more, leptin levels displayed a positive correlation with TSH levels and a negative correlation with T3 levels in TD. Overall, these findings suggested that leptin may be involved in an underlying mechanism of hypothyroidism, but not in hyperthyroidism. Besides, leptin levels in TD may be directly regulated by TSH and T3 levels, independent of BMI.

Our study showed that leptin levels were significantly higher in hypothyroidism, and not significantly altered in hyperthyroidism compared to euthyroidism. Leptin expression and secretion are regulated by a variety of hormones and body fat (BF) content. Leptin levels are higher in females than in males, due to differences in their BF (higher in females) as well as their sex hormones (estrogen and testosterone) [10]. Circulating leptin levels are directly correlated with elevated BMI [58]. Therefore, changes in BMI in TD are an important determinant of its leptin levels. It is known that TH is involved in the regulation of BMI, but whether TH has a direct effect on leptin levels remains controversial. TD provides a good model for exploring the effect of TH on leptin levels. Considering the effect of confounding factors (especially BMI) on leptin levels, we only included those studies that explicitly showed TD and euthyroidism were matched for age, gender, and BMI for sensitivity analysis. Surprisingly, the pooled results were consistent with the original results. Furthermore, our findings displayed a significant correlation between leptin levels and TH levels in TD. Hsieh et al. [41] indicated that TH was involved in regulating leptin metabolism independent of BMI and BF, and similar results were reported by Bettry et al. [59]. Also, Escobar-Morreale et al. [60] pointed out that the effect of TH on serum leptin concentration was higher than the prospected end of organism weight itself. Therefore, BMI is not the only factor affecting leptin levels in TD, which did not support the conclusions of Sreenan et al. [53]. Taken together, leptin levels in TD may be directly influenced by their TH levels, independent of BMI.

Leptin is recognized as a key neuroendocrine regulator of the HPT axis [61]. Thyrotropin-releasing hormone (TRH), a crucial peptide hormone in HPT regulation, functions as a metabolic sensor for thyroid function and energy balance regulation and is sensitive to energy balance regulators like leptin [62]. It has been reported that food deprivation (low circulating leptin concentrations) contributed to reduced TRH synthesis in the hypothalamic paraventricular nucleus (PVN), and exogenous leptin supplementation restored food deprivation-associated TRH gene expression, as well as reversing the inhibitory effect of fasting on spontaneous TSH secretion [63–65]. Specifically, leptin binds to the ObRb in the hypothalamic arcuate nucleus (ARC) or acts directly on the PVN to promote the release of TRH and thereby promote the release of TSH from the pituitary [66]. Therefore, leptin promotes energy expenditure by increasing TH levels. The above also explains why ObRb mutation can lead to central hypothyroidism [67]. However, the role of HPT on leptin remains contentious. Our study showed a positive correlation between leptin levels and TSH levels. The presence of functional TSH receptor (TSHR) in adipocytes has been demonstrated [68, 69]. Menendez et al. [70] demonstrated that TSH can act directly on adipose tissue to promote leptin secretion by employing human omental adipose tissue. Besides, Santini et al. [71] also noted that acute exogenous supplementation of TSH significantly increased serum leptin levels. Notely, Mantzoros et al. [72] pointed out that both leptin and TSH release were highly organized and pulsatile, with similar circadian rhythms and overlapping peaks, and that there was a strong positive correlation between their patterns of 24-h variability. In sum, there may be a complex positive feedback system between leptin and TSH. Moreover, leptin upregulates type 1 and 2 iodothyronine deiodinase activity in adipose tissue [73, 74]. The present study showed a negative correlation between leptin levels and T3 levels. Current evidence suggests a complex role for T3 in regulating leptin. Kristensen et al. [75] demonstrated that T3 directly inhibits leptin expression and release by human subcutaneous adipose tissue. In the periphery, leptin regulation of energy metabolism is dependent on sympathetic nervous system (SNS) activity [10]. Fain et al. [76] observed that T3 injection resulted in an increase in β-adrenergic receptor mRNA expression and a decrease in leptin mRNA expression in adipose tissue of hypothyroid rats. Kosaki et al. [77] found that treatment of 3T3-L1 adipocytes with either norepinephrine or isoprenaline suppressed leptin mRNA levels in a dose-dependent manner, which was attenuated by the addition of propranolol (β-adrenergic receptor blocker). In short, stimulation of β-adrenergic receptors decreases leptin expression and release, as evidenced in both humans and rodents [78, 79]. It is well known that T3 makes peripheral tissues hyperresponsive to adrenergic hormones. So, the action of T3 on leptin can be interpreted in the context of adipocyte β-adrenergic receptor sensitivity. Hypothyroidism and hyperthyroidism have functional hypo- and hyper-adrenergic states, respectively [80]. However, Fain et al. [81] reported that T3 stimulated or inhibited adipose tissue leptin mRNA expression, which was inhibited by T3 alone but stimulated by T3 in the presence of insulin. The negative feedback loop of insulin and leptin is known to play an essential role in maintaining nutritional homeostasis [82]. The current evidence has shown that insulin promotes the expression and release of leptin in adipose tissue [83, 84]. Notably, T3 can stimulate insulin secretion and induce hyperinsulinemia [85, 86]. Besides, elevated or lowered T3 levels can result in the development of insulin resistance [86, 87]. Peripheral insulin resistance occurs in hypothyroidism, and in hyperthyroidism, hepatic and peripheral insulin resistance are observed [86–88]. Therefore, the increases offsetting the decreases could be a plausible explanation for the lack of significant changes in leptin levels in hyperthyroidism. In sum, leptin secretion or degradation in TD may be directly affected by TSH and T3 levels.

Leptin is not only a peptide hormone that regulates energy homeostasis, but also a signaling molecule that regulates physiological equilibrium, and leptin dysregulation has been associated with a variety of diseases [12, 58]. Elevated leptin levels promote processes such as dyslipidemia, insulin resistance, inflammation, oxidative stress, vascular smooth muscle proliferation, platelet aggregation, and vascular endothelial damage, thereby accelerating the onset of metabolic diseases, cardiovascular diseases, and others [58, 89]. Additionally, chronically high leptin levels lead to the occurrence of leptin resistance, initiating a vicious positive feedback loop, further aggravating obesity and related metabolic disorders [58, 90]. Taken together, high leptin levels may be involved in increasing the risk of hypothyroidism-related complications. Therefore, monitoring leptin levels in hypothyroidism may help predict and prevent serious consequences of the disease in the future.

To our knowledge, this is the first meta-analysis to explore circulating leptin levels in TD. Additionally, we conducted sensitivity analyses to exclude confounders including age, gender, and BMI as much as possible, as well as pooled the correlations between leptin levels and TH levels to demonstrate the direct effect of thyroid function itself on leptin levels. However, it did have some limitations. Firstly, due to the cross-sectional nature of the included studies, the causal relationship between TD and leptin cannot be well illustrated. Secondly, we were unable to exclude the effect of Body fat percentage (BF%) on the results, as it was not available in most included studies. Dutta et al. [17] showed that leptin levels were significantly higher in hyperthyroidism than in euthyroidism, which may be related to the significant difference in BF%. Thirdly, the pooled results showed strong heterogeneity, although we performed meta-regression to explore the sources of heterogeneity, the results were unsatisfactory. Additionally, we did not further analyze the etiology of TD due to its diversity. Fourthly, we only included studies published in English, which may have missed suitable studies published in other languages. Given these factors, the results of our study should be interpreted with caution. Future relevant large prospective studies to verify the feasibility of our results are necessary.

Conclusion

In conclusion, circulating leptin levels were significantly higher in hypothyroidism, and not significantly altered in hyperthyroidism compared to euthyroidism. Besides, leptin levels in TD may be directly regulated by TSH and T3 levels, independent of BMI. Leptin may be a potential marker and effective therapeutic target for hypothyroidism. Future large-scale experimental studies and clinical trials to explore the potential mechanisms and clinical value of leptin in hypothyroidism are necessary.

Supplementary Information

Supplementary Material 1. (2MB, docx)

Acknowledgements

Thanks to the authors for their contributions and the support of the foundation.

Clinical trial number

Not applicable.

Abbreviations

TD

Thyroid dysfunction

HPT

Hypothalamic-pituitary-thyroid

TRH

Thyrotropin-releasing hormone

TH

Thyroid hormone

TSH

Thyroid-stimulating hormone

T4

Thyroxine

T3

Triiodothyronine

FT4

Free thyroxine

FT3

Free triiodothyronine

TSHR

Thyroid-stimulating hormone receptor

BMR

Basal metabolic rate

BMI

Body mass index

BF

Body fat

BF%

Body fat percentage

Ob

Obesity

ObRb

Leptin receptor

RIA

Radioimmunoassay

ELISA

Enzyme-linked immunosorbent assay

PVN

Paraventricular nucleus

ARC

Arcuate nucleus

SNS

Sympathetic nervous system

SMD

Standardized mean difference

CI

Confidence interval

ES

Effect size

R

Correlation coefficient

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

NOS

Newcastle Ottawa Scale

AHRQ

Healthcare Research and Quality Scale

Authors’ contributions

All authors were involved in the conception and design of the study. SL, JM, LZ, and YY completed the data preparation, data extraction, and data analysis. SL wrote the first draft. The draft was reviewed and revised by LT and ZH. All authors read and finalized the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China [No. 82060152] and the Natural Science Foundation of Gansu Province [No. 22JR5RA648].

Data availability

All available data analyzed in this study are included in the manuscript and its supplementary materials.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Data Availability Statement

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