REVIEW
The effect of acromegaly on thyroid disease
2023 年 70 巻 11 号 p. 1051-1060
詳細
2023 年 70 巻 11 号 p. 1051-1060
Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.
Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) regulate the growth, development, and function of many tissues in the human body. However, excessive GH levels in adults are manifested as acromegaly. Excessive GH secretion stimulates the liver to produce IGF-1, which leads to characteristic clinical symptoms and signs, such as soft tissue thickening, changes in facial appearance, headache, visual disturbances, and joint lesions. More than 95% of clinical cases of acromegaly occur because of GH-secreting pituitary adenoma (GHPA) [1]. Nevertheless, data on the incidence and prevalence of acromegaly are not uniform across countries and regions. In Europe, the prevalence and annual incidence of the disease are 2.8–13.7/100,000 and 0.2–1.1/100,000, respectively [2]. In the United States, the overall annual incidence and prevalence of acromegaly are approximately 1.1/100,000 and 7.8/100,000, respectively [3]. Moreover, the prevalence and annual incidence of GHPA in Japan are 9.2/100,000 and 0.49/100,000, respectively [4]. Long-term exposure to higher GH and IGF-1 levels increases the risk of insulin resistance, diabetes, dyslipidemia, hypertension, hypertrophic cardiomyopathy, and sleep apnea. However, the existing studies have shown remarkably different effects of high serum GH and IGF-1 levels in patients with acromegaly on the thyroid structure and function. Most studies have indicated that the long-term stimulation of the follicular epithelium by GH and IGF-1 can lead to thyroid dysfunction, goiter, thyroid nodules, thyroid cancer, and thyroid-associated ophthalmopathy (TAO). Therefore, herein, we present an overview of the effects of high GH/IGF-1 levels in patients with acromegaly on thyroid diseases (Fig. 1).
The relationship between high GH/IGF-1 and thyroid disease
Long-term stimulation of the thyroid follicular epithelium by high GH and IGF-1 can cause thyroid dysfunction, benign hyperplasia (including goiter and thyroid nodules), and even thyroid cancer. TSHR/IGF-1R in orbital fibroblasts crosstalk to form a functional complex, and activated orbital fibroblasts can also proliferate and differentiate into adipocytes and myofibroblasts, which further increase orbital tissue volume, resulting in TAO. There are two pathways for the secretion of HA, one is a TSHR-dependent and IGF-1R-independent pathway, and the other is a TSHR-dependent and IGF-1R-dependent pathway. IGF-1R antagonists can only partially inhibit stimulation by the monoclonal TSHR-stimulating antibody M22, whereas TSHR antagonists can inhibit both phases of M22 stimulation.
Abbreviation: GHRH, growth hormone releasing hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone; TSHR, thyroid stimulating hormone receptor; GH, growth hormone; T3, triiodothyronine; T4, thyroxine; IGF-1, insulin-like growth factor-1; IGF-1R insulin-like growth factor-1 receptor; HA, hyaluronic acid; TAO, thyroid-associated ophthalmopathy.
Most patients with acromegaly exhibit normal thyroid functions, whereas some may have hypothyroidism, and a few may have hyperthyroidism. Natchev found a 39% prevalence of thyroid dysfunction in 146 patients with acromegaly [5]. Another retrospective study of 116 patients with acromegaly showed that 12.3% of the patients had primary hypothyroidism, whereas 3.5% had primary hyperthyroidism [6]. A cross-sectional study on 139 newly treated patients with non-functioning pituitary adenoma (NFPA) and 150 patients with GHPA showed that serum thyroid-stimulating hormone (TSH) levels were significantly lower, whereas free triiodothyronine and free thyroxine (FT4) levels were significantly higher in the 150 patients than in the 139 patients. Serum FT4 and TSH levels were positively and negatively correlated with IGF-1 levels, respectively [7].
Animal studies have also confirmed that GH/IGF-1 levels affect thyroid functions. Compared with normal mice, GH receptor knockout mice exhibited a reduced thyroid follicular surface area and follicular perimeter, and a trend toward reduced follicular epithelial thickness, suggesting GH signaling as a key pathway in thyroid growth and function regulation [8]. Another study found that serum T4 concentrations were reduced by 30% in 5-week-old thyrocyte-selective ablation of IGF-1 receptor (TIGF1RKO) mice, and the expression of monocarboxylate transporter 8 involved in T4 secretion was down-regulated by 43%, suggesting that IGF-1 receptor deficiency in thyroid cells impaired thyroid hormone secretion [9].
Acromegaly treatment can also affect thyroid functions. Somatostatin (SST) receptor ligands (SRLs), commonly used to treat patients with acromegaly, have central and direct effects on thyroid functions. SRLs inhibit thyroid-stimulating cell proliferation and TSH secretion at the pituitary level; thus, they can be used to treat TSH-secreting pituitary adenomas [10]. Furthermore, thyroid cells express SST receptors (SSTRs) at the thyroid level. A case of a woman with severe Graves’ disease with acromegaly was presented in a previous report, where the coexistence of acromegaly aggravated the severity of Graves’ disease, and the activity indices, symptoms, and signs of Graves’ disease improved after the surgical remission of acromegaly [11]. Nomoto et al. [12] reported a case of a woman with typical physical features of acromegaly, who presented with autonomously functioning thyroid nodules, and thyrotoxicosis with TSH suppression was also confirmed. After octreotide treatment, IGF-1 levels and thyroid function returned to normal.
Scholars have proposed different mechanisms to explain the effect of high GH/IGF-1 levels on thyroid functions, especially TSH (Fig. 2). They are described below.
Mechanisms by which high GH/IGF-1 affects thyroid function
(1) Increased peripheral deiodination of T4 to T3 conversion. (2) Decreased leptin secretion. (3) Decreased sympathetic nerve activity. (4) Decreased secretion of somatostatin. (5) TSHR and IGF-1R crosstalk.
Abbreviation: TRH, thyrotropin-releasing hormone; SST, somatostatin; SSTR, somatostatin receptors; GHRH, growth hormone-releasing hormone; TSH, thyroid stimulating hormone; GH, growth hormone; DIO2, type 2 deiodinases; T3, triiodothyronine; T4, thyroxine; TSHR, thyroid stimulating hormone receptor; IGF-1, insulin-like growth factor-1; IGF-1R insulin-like growth factor-1 receptor.
The single deiodination of T4 to T3 (activation pathway) is catalyzed by type 1 deiodinases (DIO1) and type 2 deiodinases (DIO2). Thyroid hormone feedback to thyrotropin-releasing hormone (TRH) is regulated by the local conversion of T4 to T3 by DIO2. An increase in the conversion of extrathyroidal T4 to T3 is mediated by GH [13]. In vitro, GH significantly increases DIO2 expression at the mRNA level in HTC/C3 cells (p < 0.01), as well as DIO2 protein and its activity, suggesting that the mechanism by which GH affects thyroid functions is related to DIO2 gene upregulation [14].
Decreased leptin secretionLeptin directly and indirectly stimulates TRH synthesis and release, respectively [15]. Roelfsema has suggested that the decreased synthesis and secretion of TSH in patients with active acromegaly may be related to the inhibition of leptin translocation to the paraventricular nucleus because leptin levels decrease in patients with active acromegaly [16]. Conversely, leptin secretion in pituitary adenomas may increase after surgery and SRL or GH receptor antagonist treatment [17].
Decreased sympathetic nerve activitySympathetically innervated cardiac activity decreases in patients with acromegaly [18]. Animal experiments have shown decreased sympathetic responses in transgenic mice overexpressing the bovine GH gene [19]. Furthermore, some studies have shown decreased basal and pulsatile TSH secretion in patients with active acromegaly; however, their T4 levels remained the same. This outcome may be related to reduced sympathetic nerve functions when excess GH is present, which increases thyroid responsiveness to TSH [16].
Decreased secretion of SSTHypothalamic GH-releasing hormone (GHRH) stimulation and SST inhibition balance pituitary GH production. Hypothalamic SST reduces TSH secretion by activating SSTR2 and SSTR5 in thyroid cells [20]. Therefore, high GH levels may regulate TSH secretion via the negative feedback inhibition of SST production. However, because GHRH increases the TSH-releasing effect of TRH in healthy men and patients with acromegaly, decreased GHRH release may also decrease the TSH-releasing effect of TRH [21].
TSH receptor (TSHR) and IGF-1 receptor (IGF-1R) crosstalkTSHR and IGF-1R co-localize and co-immunoprecipitate in orbital fibroblasts, orbital adipocytes, and primary human thyroid epithelial cells, forming a functional complex. Tsui has reported that the anti-IGF-1R inhibitory antibody 1H7 attenuates signaling initiated by recombinant human TSH and immunoglobulin G in vitro in Graves’ disease [22]. Other studies have shown that the conditional knockout of IGF-1R in the thyroid reduces its responsiveness to TSH [9].
Goiter is a common disease in patients with acromegaly. A prospective study showed that patients with acromegaly had significantly higher thyroid volume (TV) than those without acromegaly (median: 12.5 mL vs. 6.3 mL, p < 0.0001) [23]. A study on 129 patients with acromegaly and 247 controls showed that 93 (72.1%) patients with acromegaly exhibited thyroid lesions, and diffuse (14.7%) and multinodular goiters (47.3%) were significantly higher in the acromegaly group than in the control group [24]. Additionally, Reverter found that the incidence of goiter was higher in the patient group than in the control group (24.9% vs. 8.3%, respectively, p < 0.001) [25].
Goiter occurrence in patients with acromegaly is correlated to GH/IGF-1 levels. A study performed thyroid ultrasound in 106 patients with acromegaly, including 11 with diffuse goiter, 42 with nodular goiter, and 22 with nonspecific morphological abnormalities. The TV was larger in patients with active acromegaly and was positively correlated with GH, IGF-1, and IGF-1 standard deviation scores [26]. A study found that patients with active acromegaly exhibited a goiter rate of 87% and significantly increased TV (38.5 ± 45.4 mL vs. 27.2 ± 18.4 mL, p = 0.036). A weak positive correlation was observed between TV and IGF-1 in the whole group and female patients (r = 0.218, p = 0.013 and r = 0.238, p = 0.037, respectively) [5]. Another study showed that of 93 patients with acromegaly, 72 (77.4%) exhibited abnormal thyroid morphology. Furthermore, patients with high random GH levels (p = 0.01), trough GH levels (p = 0.008), and IGF-1 levels (p = 0.018) showed significantly larger TVs. The GH levels of patients with abnormal thyroid morphology were significantly higher than those of the normal controls (p = 0.036) [27].
Animal studies have shown that in addition to TSH, the primary regulator of thyroid hormone production and thyroid growth, IGF-1 signaling affects thyroid functions and growth. In 5-week-old mice, the area of thyroid cells in wild-type (WT) mice increased by 40% 10 days after TSH injection, whereas that in TSH-injected TIGF1RKO mice did not increase. The WT mice treated with methimazole and sodium perchlorate for 2 or 6 weeks developed noticeable goiters (2.0 and 5.4-fold, respectively); however, this goiter development was completely suppressed in the TIGF1RKO mice, suggesting an essential role of IGF-1R signaling in regulating thyroid functions and TSH-stimulated goitrogenesis [9]. An in vitro study showed that IGF-1 promoted thyroid cell proliferation and secretory functions in time- and dose-dependent manners by promoting the transition of the cell cycle from the G1/S phase to the G2/M phase and inhibiting apoptosis [28].
Goiter in patients with acromegaly can be reversed by lowering GH/IGF-1 levels to normal with the help of surgery or medication. Herrman et al. [29] reported an increase in TV of up to 20% in patients with active acromegaly and a reduction in TV of approximately 25% following cabergoline treatment and surgery. A study showed that patients with acromegaly had significantly greater TV than those shown by patients in the NFPA (18.32 mL vs. 9.91 mL, p < 0.001) and control groups (18.32 mL vs. 9.63 mL, p < 0.001). At follow-up, the median TV in the cured group (n = 20, p = 0.003) decreased from 22.74 to 17.87 mL. These changes in the TV were significantly associated with IGF-1 levels (r = 0.37, p = 0.029) [28].
A meta-analysis showed that compared with controls, patients with acromegaly exhibited a significantly higher incidence of thyroid nodular disease (TND) (odds ratio [OR] = 6.9, risk ratio = 2.1), with a mixed prevalence of TND of 59.2% [30]. The Liège Acromegaly Survey database comprising 3173 patients with acromegaly from 10 countries showed that thyroid nodules were common (34.0%) in patients with acromegaly [31]. Can et al. found that the incidence of thyroid nodules and the number of nodules were significantly higher in the acromegaly group than in the control group (55.4% vs. 35.7%, p = 0.038 and 1.27 ± 1.43 vs. 0.48 ± 0.73, p = 0.003) [32]. Dogansen [33] included 138 patients with acromegaly in a study, and after 7 years of follow-up, 69% of the patients developed TND, and the baseline IGF-1 upper limit of normal was higher in patients with TND (p = 0.01). Nodular growth was more significant in patients with active acromegaly (p < 0.001). For one unit change in the IGF-1 levels, nodule growth increased by 1.01 folds and presence of active acromegaly disease was related with nine-fold increase in nodule growth.
The occurrence of thyroid nodules in patients with acromegaly is associated with the disease course. A study found that among 240 patients with acromegaly, 56 (80%) had thyroid nodules, and the longer the course of acromegaly, the higher the risk of thyroid nodules (OR = 1.306, 95% confidence interval (CI) [1.010–1.688], p = 0.035) [34]. Another study investigated 92 patients with acromegaly for more than 12 years. Of the 64 patients with palpable nodular or diffuse goiter who underwent thyroid ultrasonography in the follow-up after treatment, 44 (47.8%) presented with thyroid nodules. A longer disease duration (14.2 ± 6.6 years) was observed in patients with the nodules than in patients without the nodules (9.4 ± 3.4 years, p = 0.043) [35].
Acromegaly treatment can improve thyroid nodules. A study on 134 patients with GHPA and NFPA showed that the number of hypoechoic, isoechogenic, heterogeneous, and vascular thyroid nodules in patients with GHPA along with thyroid disease was significantly higher than that in patients with NFPA along with thyroid disease. In the cured group, the morphology of solid nodules improved and the number of heterogeneous and vascular thyroid nodules decreased significantly compared with those before the surgery [36]. Another study [37] selected 43 patients who did not meet the criteria for remission after surgery, and they were treated with SRLs for at least 6 months and had normal thyroid functions. The total thyroid nodule volume (TTNV) was significantly lower in patients with well-controlled acromegaly (0.44 [0.75] to 0.23 [0.73], p < 0.001). No significant change was observed in TTNV in the control group (0.18 [1.28] to 0.13 [1.54], p = 0.959), whereas the TTNV increased in patients with active acromegaly (0.77 [1.46] to 1.03 [1.88], p = 0.028). The successful treatment of patients with active acromegaly reduces the thyroid nodule volume, indicating that thyroid nodules can change dynamically according to the activity of acromegaly; thus, nodule growth should be closely monitored in such patients to prevent the risk of cancer progression.
Multiple studies have shown that compared with the general population, patients with acromegaly are at an increased risk of developing tumors, the most common of which is thyroid cancer, mainly papillary carcinoma, which may be related to the deleterious effects of high GH/IGF-1 levels in acromegaly. High GH/IGF-1 levels promote tumorigenesis by promoting cell proliferation, abnormal cell growth, and angiogenesis and inhibiting apoptosis. However, current data on thyroid cancer incidence in patients with acromegaly are inconsistent (Table 1).
Summary of thyroid nodules and cancer incidence in patients with acromegaly
| References | Year | Patients n (% females) | Age (year) | Patients with TND n (%) | Patients with TC n (%) | Controls | Mean follow-up (year) |
|---|---|---|---|---|---|---|---|
| Slightly elevated or not elevated | |||||||
| Baldys-Waligorska et al. [41] | 2010 | 101 (71/70.3%) | 51.8 ± 15.4 | 64 (63%) | 3 (3.0%) | 9.4 ± 6.5 | |
| Uchoa et al. [26] | 2013 | 106 (62/58.5%) | 46.5 | 42 (39.6%) | 4 (3.8%) | 1 | |
| Dogan et al. [35] | 2014 | 92 (49/53.3%) | 43.9 ± 10.8 | 44 (47.8%) | 5 (5.4%) | 12 | |
| Lai et al. [43] | 2020 | 221 (109/49.3%) | 53.8 ± 15.2 | 71 (32.1%) | 6 (2.7%) | ||
| Park et al. [42] | 2020 | 718 (407/56.7%) | 46.0 | 38 (5.3%) | 7,180, the general population | ||
| Cankurtaran et al. [24] | 2021 | 129 (78/60.5%) | 40.7 ± 12.5 | 71 (57.4%) | 9 (7.0%) | 247, non-acromegalic patients | |
| Significantly increased | |||||||
| dos Santos et al. [44] | 2013 | 124 (76/61.3%) | 45.1 | 67 (54%) | 9 (7.2%) | 263, non-functioning or PRL secreting adenomas | |
| Dagdelen et al. [45] | 2014 | 160 (79/49.4%) | men (49.1 ± 12.4), women (52.0 ± 10.4) | 106 (72.1%) | 17 (10.6%) | 7.1 ± 5.7 | |
| Mian et al. [48] | 2014 | 113 (63/55.8%) | 56 ± 14 | 70 (61.9%) | 12 (11%) | 11.1 ± 8.7 | |
| Kaldrymidis et al. [49] | 2016 | 110 (62/56.4%) | 58.63 ± 13.8 | 13 (11.8%) | |||
| Dogansen et al. [33] | 2019 | 138 (73/52.9%) | 95 (69%) | 15 (11%) | 7 | ||
| Sema et al. [46] | 2020 | 138 | 43.35 ± 11.06 | 14, papillary thyroid cancer patients without acromegaly | |||
Abbreviation: TND, thyroid nodular disease; TC, thyroid cancer; PRL, prolactin.
Some studies have suggested that thyroid cancer prevalence in patients with acromegaly is not significantly different or only slightly increased compared with that observed in the general population. A study on 129 patients with acromegaly and 247 controls showed no significant difference in thyroid cancer prevalence between the two groups [24]. An analysis of the German Acromegaly Registry has shown that thyroid cancer incidence was not higher in patients with acromegaly than in the normal population [38]. A study on 106 patients with acromegaly showed that thyroid cancer occurred in only four patients (3.8%) [26]. In a study by Gullu, the malignancy detection rate was 15% (16/105), and thyroid cancer was the most common cancer (4.7%, 5/105) [39]. Kadioglu et al. found a 6% incidence of thyroid cancer in 313 patients with acromegaly [40], whereas Baldys-Waligorska found a 3% prevalence of thyroid cancer (3/101) [41]. Another retrospective study on 92 patients with acromegaly, who were followed up for more than 12 years, showed that 7.8% of the patients were diagnosed with thyroid cancer based on the thyroid ultrasound results [35]. The results of a longitudinal case-control study that included 718 patients with acromegaly and 7,180 controls showed that 61 patients with acromegaly developed malignant tumors (8.5%), of which thyroid cancer was the most common disease (n = 38, 5.3%) [42]. A retrospective study in the United States [43] showed that 8.5% of all nodules observed in patients with acromegaly were thyroid cancer, which is similar to the general US population with thyroid nodules (7–15%). The study concluded that routine screening of thyroid ultrasonography is of minimal benefit in patients with acromegaly and should be reserved for those with remarkable thyroid nodules.
Acromegaly significantly increases thyroid cancer riskHowever, Santos found [44] that thyroid cancer prevalence increased significantly in patients with acromegaly compared with that in controls. The study included 124 patients with acromegaly and 263 age- and sex-matched control subjects. Thyroid cancer occurred in nine patients with acromegaly (7.2%) and only two (0.7%) in the control group (p = 0.0011, 95% CI [2.17–48.01]). Dagdelen included 160 patients with acromegaly with a mean follow-up of 7.1 ± 5.7 years and the results showed that malignant tumors were found in 34 patients (21.3%), with the most common tumor being thyroid cancer (n = 17, 10.6%) [45]. Sema reported thyroid cancer in 14 (10%) of 138 patients [46], and Doğanşen found thyroid cancer in 15 (11%) of 138 patients with acromegaly [33]. A meta-analysis of cancer standard incidence rates (SIRs) performed by Dal in patients with acromegaly showed a significantly increased incidence of thyroid cancer (SIR = 9.2, 95% CI [4.2–19.9]) [47]. Furthermore, a study showed 12 differentiated thyroid cancers (11%) in 113 patients with acromegaly [48]. Of 110 patients with acromegaly evaluated for cancer risk, 26 (23.6%) were diagnosed with cancer, with thyroid cancer being the most common type, diagnosed in 13 (11.8%) [49]. Therefore, effective therapeutic strategies should be implemented to normalize GH/IGF-1 levels to reduce the morbidity and mortality of malignancy in patients with acromegaly. Routine thyroid ultrasonography and regular cancer screening, especially thyroid cancer, are recommended for patients with acromegaly. Moreover, patients with persistently high IGF-1 levels should undergo regular thyroid examination, including ultrasound-guided fine-needle aspiration biopsy, especially if nodules with malignant propensity are identified on ultrasound. In addition, the increased number of thyroid cancer diagnoses in patients with acromegaly may be because they are being tested more accurately and more frequently than before.
High IGF-1 levels may increase the risk of malignancy owing to the mitotic properties at the tissue level. Liu et al. [50] reported higher IGF-1 and IGF-1R mRNA and protein levels in the thyroid tissues of patients with follicular adenoma, nodular goiter, and papillary thyroid carcinoma than in the controls. Furthermore, a study on serum levels of IGF-1 and insulin-like growth factor-2 (IGF-2) in patients with papillary thyroid carcinoma showed that serum levels of 63% of IGF-1 and 85% of IGF-2 in patients with papillary thyroid carcinoma may be higher than those in controls [51]. Some scholars [52] studied thyrocyte-specific insulin receptor (IR) and IGF-1R double knockout (DTIRKO) mice. Neonatal DTIRKO mice showed smaller thyroid glands. Deletion of IR and IGF-1R paradoxically induced thyroid cell proliferation at postnatal day 14, and by week 50, all DTIRKO mice developed papillary thyroid carcinoma-like lesions that were associated with ErbB pathway induction. The results revealed an important interplay of IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and papillary carcinoma, suggesting that the IGF signaling pathway plays an essential role in the occurrence and development of papillary thyroid carcinoma, and its components can be considered potential diagnostic and prognostic markers for the disease and targets for anticancer therapy.
TAO is an autoimmune disease often associated with orbital inflammation, fibrosis, and adipose expansion. Clinically manifested as eyelid retraction, proptosis, eye swelling, periorbital edema, and eye movement disturbances, which can result in visual impairment and reduce the quality of life, and are often ineffective against various treatments. A recent population-based study in the United States reported a TAO incidence of 2.9/100,000/year in men and 16/100,000/year in women [53]. Conventional glucocorticoid therapy (oral, intravenous, or local orbital injection) and radiation therapy are the mainstay of therapy to reduce retroorbital tissue inflammation and prevent fibrosis. These therapies provide temporary relief of symptoms and do not exert a sustained and marked effect on disease prognosis or reverse the underlying pathophysiological mechanisms. Additionally, long-term steroid treatment exerts considerable side effects. Thus, owing to the absence of effective medical therapy, surgery is the only ultimate option once the inflammation subsides.
Though TAO pathogenesis has not been fully elucidated, existing theories suggest that TSHR plays a key role in the occurrence and development of TAO [54]. However, anti-TSHR autoantibodies alone cannot explain the presence of disease in euthyroid or hypothyroid TAO patients, suggesting that another receptor may play a role in the pathogenesis of TAO, such as IGF-1R [55]. A study showed that TSHR and IGF-1R levels in the orbital connective tissues of patients with TAO were higher than those in normal tissues. Tsui found a physical and functional complex consisting of TSHR and IGF-1R in orbital fibroblasts obtained from patients with TAO [22]. Thus, owing to the current improved understanding of TAO pathophysiology, the TAO treatment focus has been shifted to targeted biotherapeutics. Biologics exert precise immunomodulatory effects and have better safety and efficacy profiles than those of traditional methods.
IGF-1RA case report [56] described an adult patient with GH deficiency who developed bilateral lacrimal gland and eyelid swelling after a month of GH therapy initiation and was diagnosed with TAO. Withdrawal of GH administration alone relieved orbital compression, and glucocorticoids and radiation therapy further improved the condition. Therefore, GH/IGF-1 hyperactivity was considered a risk factor for TAO. Growing evidence confirms that IGF-1R is overexpressed in TAO, anti-IGF-1R antibodies that block orbital fibroblast signaling exist in patients with TAO, and orbital fibroblasts from patients with TAO produce hyaluronic acid (HA) induced by thyroid-stimulating immunoglobulin and IGF-1 [57]. Clinical trials on IGF-1R inhibitors for TAO treatment are ongoing. Teprotumumab is a fully human monoclonal IGF-1R antagonist that can reduce proinflammatory cytokine production, HA secretion, and orbital fibroblast activation in patients with TAO by inhibiting the IGF-1R/TSHR signaling pathway [58]. Based on a published phase 2 trial, teprotumumab changed disease endpoints in patients with active TAO. The results of a 24-week randomized, placebo-controlled study of patients with active, moderate, and severe TAO showed a statistically significant reduction in the primary composite endpoint (defined as proptosis [a reduction of ≥2 mm] and clinical activity score ≥2 point reduction on a 7-point scale) versus placebo [59]. Teprotumumab has now been approved for ophthalmopathy treatment, and the drug has revolutionized TAO treatment [58, 60].
TSHR and IGF-1R crosstalkThe in situ immunostaining of orbital tissues revealed that IGF-1Rβ or TSHR immunoprecipitation in human orbital fibroblasts, orbital adipocytes, or thyroid cells produced insoluble complexes that contained both receptors. IGF-1R levels were significantly higher in TAO orbital fibroblasts than in control donors. After IGF-1 treatment, TSHR expression on the surface of orbital fibroblasts obtained from patients with TAO increased, whereas its expression did not change significantly in the controls [22]. Furthermore, TSHR protein and mRNA levels increased after IGF-1 treatment. Compared with cells treated with TSH alone, IGF-1 pretreatment increased TSH-induced cyclic adenosine monophosphate production. These results suggest that IGF-1 enhances functional TSHR expression on the cell surface by increasing TSHR expression and inducing TSHR translocation to the plasma membrane of orbital fibroblasts in patients with TAO. Additionally, IGF-1R antagonists inhibit TSH signaling, thus supporting the interaction between TSHR and IGF-1R. Tsui [22] reported that the IGF-1R blocking antibody 1H7 inhibited the TSH-mediated activation of mitogen-activated protein kinase 1 or extracellular signal-regulated kinase in thyroid cells. The IGF-1 pathway cooperates with TSH to promote thyroid cell growth. The autoantibody activation of the TSHR/IGF-1R complex results in downstream gene expression. Additionally, activated orbital fibroblasts can proliferate and differentiate into adipocytes and myofibroblasts, further increasing orbital tissue volume. These data suggest that TAO is caused by glycosaminoglycan accumulation due to TSHR/IGF-1R complex upregulation in orbital fibroblasts from susceptible individuals, including the production of HA in the orbit and the expansion of adipose and muscle volumes near the orbit.
In many studies, the activation of TSHR- and IGF-1R-stimulated HA secretion has been considered a biological response because increased orbital HA secretion is a major component of TAO pathophysiology. HA can be secreted via two pathways, one is a TSHR-dependent and IGF-1R-independent pathway, whereas the other is a TSHR-dependent and IGF-1R-dependent pathway. A major indication of TSHR/IGF-1R interaction is that simultaneous activation of TSH and IGF-1 can synergistically increase HA secretion. IGF-1R antagonists, such as the small-molecule antagonist linsitinib or the anti-IGF-1R antibody 1H7, inhibit TSH-stimulated HA secretion, whereas they partially inhibit stimulation by the monoclonal TSHR-stimulating antibody M22 because the antagonism affects only the high-potency phase of stimulation [61]. Conversely, the TSHR antagonist ANTAG3 (NCGC00242364) can completely inhibit M22-stimulated HA secretion, that is, TSHR antagonists inhibit both stages of M22 stimulation. These results suggest that treatment strategies targeting both, TSHR and IGF-1R, may be advantageous over treatment strategies targeting either of the two receptors alone. Specifically, combination therapy may be an effective strategy to reduce drug doses and/or compensate for the loss of therapeutic effects on either receptor.
The relationship between the GH/IGF-1 and hypothalamic-pituitary-thyroid axes has been evaluated but is quite complex. GH/IGF-1 supports normal thyroid functions, volume, and hormone synthesis. Some of these effects are mediated by increased sensitivity to TSH effects, whereas others are probably independent of pituitary functions. GH/IGF-1 is also involved in thyroid pathological states, including benign thyroid enlargement and thyroid cancer. Thus, every patient with acromegaly is recommended to undergo hormonal and imaging evaluation of the thyroid at the time of diagnosis and accurate evaluation during further observation and treatment, which is particularly important for the early diagnosis and exclusion of thyroid cancer. In TAO, the IGF-1R inhibitor teprotumumab can reduce pro-inflammatory cytokine production, HA secretion, and orbital fibroblast activation and has a good clinical application prospect. However, a combination therapy targeting TSHR and IGF-1R may have advantages over a therapy targeting either of the two receptors alone.
The authors declare that they have no conflict of interest.
