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Annales d'Endocrinologie
Volume 77, n° 1
pages 37-42 (février 2016)
Doi : 10.1016/j.ando.2015.10.008
High prevalence of autoimmune thyroid diseases in patients with prolactinomas: A cross-sectional retrospective study in a single tertiary referral centre
Forte prévalence des maladies autoimmunes de la thyroïde chez les patients atteints de prolactinome : étude transversale rétrospective monocentrique dans un centre de référence tertiaire
 

Atanaska Elenkova a, , Patrick Petrossians b, Sabina Zacharieva a, Albert Beckers b
a University Hospital of Endocrinology, Medical University, Sofia, Bulgaria 
b University of Liege, CHU of Liege, Department of Endocrinology, Liege, Belgium 

Corresponding author.
Abstract
Background

Prolactin has been shown to exert potent immunomodulatory activities.

Design

Retrospective cross-sectional study examining the prevalence of autoimmune thyroid diseases (AITD) in patients with prolactinomas. The medical files of 462 patients (367 women and 95 men) followed up at a single tertiary referral centre were analyzed.

Results

The prevalence of AITD among prolactinoma patients was estimated at 21.0% (23.2% in females and 12.6% in males). In 51.5% of the patients, diagnosis of prolactinoma preceded the development of AITD; in 37.2%, both diseases were simultaneously diagnosed and 11.3% of patients were diagnosed first with AITD. Hyperthyroidism was observed in 1.24% of the investigated subjects. Primary hypothyroidism was detected in 15.6% of all patients (16.4% in women; 10.7% in men) with a mean incidence of 24 cases/1000/year.

Conclusions

Our results demonstrate the high frequency of AITD in patients with prolactinomas. The prevalence rate of hyperthyroidism is comparable with the literature data from community-based studies. In contrast, the prevalence of the spontaneous hypothyroidism due to autoimmune thyroiditis is significantly higher in female and male subgroups of patients with prolactinomas in comparison with the general population. A possible role of supraphysiologically increased prolactin levels in the pathogenesis and the clinical course of AITD in patients with prolactinomas can be suggested. Based on these findings we recommend routine screening for AITD with simple thyroid tests (TSH, TPO-Abs and ultrasound examination) in all patients diagnosed with prolactinoma.

The full text of this article is available in PDF format.
Résumé
Introduction

Une puissante activité immunomodulatrice a été démontrée pour la prolactine.

Méthodes

Étude rétrospective transversale étudiant la prévalence des maladies autoimmunes de la thyroïde (AITD) chez les patients atteints de prolactinome. Les dossiers médicaux de 462 patients (367 femmes et 95 hommes) suivis dans le centre de référence tertiaire ont été analysés.

Résultats

La prévalence des AITD chez les patients atteints de prolactinome a été estimée à 21,0 % (23,2 % chez les femmes et 12,6 % chez les hommes). Chez 51,5 % des patients le diagnostic de prolactinome précédait le développement des AITD ; chez 37,1 % d’entre eux, les deux maladies ont été diagnostiquées simultanément tandis que 11,3 % des patients avaient en premier lieu un diagnostic d’AITD. Une hyperthyroïdie a été observée chez 1,24 % des sujets étudiés. Une hypothyroïdie primaire a été retrouvée chez 15,6 % de l’ensemble des patients (16,4 % chez les femmes ; 10,7 % chez les hommes) avec une incidence moyenne de 24 cas/1000/année.

Conclusions

Nos résultats démontrent la fréquence élevée des AITD chez les patients souffrant de prolactinome. Le taux de prévalence de l’hyperthyroïdie est comparable avec les données de la littérature à partir d’études communautaires. En revanche, la prévalence de l’hypothyroïdie spontanée due à une thyroïdite autoimmune est significativement plus élevée dans les sous-groupes femelle et mâle de patients atteints de prolactinome par rapport à la population générale. Une augmentation supraphysiologique des taux de prolactine dans la pathogenèse et l’évolution clinique des AITD chez les patients atteints de prolactinome peut être suggérée. En nous fondant sur ces résultats, nous recommandons le dépistage systématique des AITD avec des tests simples de la thyroïde (TSH, TPO-ABS et échographie) chez tous les patients avec un diagnostic de prolactinome.

The full text of this article is available in PDF format.

Keywords : Autoimmunity, Prolactin, Thyroid diseases, Hyperprolactinemia, Prolactinoma

Mots clés : Autoimmunité, Prolactine, Maladies thyroïdiennes, Hyperprolactinémie, Prolactinome


Introduction

Over the past two decades considerable evidence has been accumulated indicating that prolactin can act as a potent immunomodulator. This hormone has been shown to influence both humoral and cell-mediated responses through binding to its specific receptors which are expressed on monocytes, macrophages, T- and B-lymphocytes, natural killer cells (NK), granulocytes and thymic epithelial cells [1, 2, 3]. Experimental studies have demonstrated that prolactin enhances lymphocytes proliferation, activates T-lymphocytes via positive regulation of interleukin-2 (IL-2) and interferon regulatory factor-1 (IRF-1) genes and increases IFN-γ production from NK cells and T lymphocytes [4, 5, 6]. Hyperprolactinemia ameliorates the synthesis of IL-4 and IL-6 that are crucial for the B lymphocytes clonal expansion, growth, differentiation and maturation [7, 8]. In accordance with these data hyperprolactinemia has been observed in many multi-organ and organ-specific autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS), Hashimoto's thyroiditis (HT) and celiac diseases [9, 10, 11, 13, 12]. Furthermore, a significant correlation has been reported between the PRL levels and the clinical disease activity of SLE and celiac disease [14, 15, 16]. On the other hand, only two small studies have been published investigating the prevalence of thyroid dysfunction and autoimmunity among patients with hyperprolactinemia compared to sex- and age-matched control subjects [17, 18].

Patients and methods
Objective

The aim of this study was to determine the prevalence of autoimmune thyroid diseases (AITD) in an unselected population of patients with prolactinomas.

Study design

A retrospective cross-sectional study was conducted at a single tertiary referral centre. Two main data sources were used: the electronic medical records (Omni Pro Hospital Information System) and the paper patients’ files (Hospital Archives).

Inclusion criteria

Subjects18 years old with diagnosis prolactinoma based on current guidelines [19, 20].

Exclusion criteria

The exclusion criteria were:

hyperprolactinemia of non tumoral origin;
negative pituitary imaging (CT, MRI);
patients having had a single visit to the hospital;
subjects coded as dead before cohort enrolment.

Additional exclusion criteria concerning the analysis of thyroid function

The additional exclusion criteria concerning the analysis of thyroid function were:

hypopituitarism (in spite of the severity and the number of anterior pituitary hormone deficits; except the isolated transient hyperprolactinemic hypogonadotropic hypogonadism);
past history of thyroid surgery;
radiation of the neck region;
previous or concomitant use of drugs with possible impact on thyroid function (iodine, lithium, etc.).

The diagnosis AITD was based on the presence of at least two of the following criteria: abnormal thyroid ultrasound pattern–diffuse non homogenous hypoechogenic structure with or without nodular changes; positive anti-thyroid peroxidase (TPO-Ab), anti-thyroglobulin (TG-Ab) and/or anti-TSH-rеceptor antibodies (TRAb); abnormal thyroid function estimated on data for serum concentrations of thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Subclinical hyperthyroidism was defined as a low or undetectable serum TSH with values within the normal reference range for both FT4 and FT3 [21]. The presence of suppressed TSH levels in a combination with elevated FT4 and FT3 levels is considered overt hyperthyroidism. Subclinical hypothyroidism was defined as an increased TSH above the upper normal limit with normal FT4 and FT3 values. Cases with elevated TSH levels and thyroid hormones value under the lower normal range were categorized as having an overt hypothyroidism. Levels of TPO-Ab and of TG-Ab above the upper limit of normal range were considered positive.

Statistical analysis

Patient data were encoded in a modified version of the LAS database adapted for this study [22]. Data analysis was performed using SPSS version 16.0 (SPSS. Inc., Chicago, Il., USA) and the R software package [23]. Continuous variables were described by arithmetic mean and standard deviation (in cases with Gaussian distribution) or median and interquartile range IQR (when data distribution was not normal). Non-metric variables were presented by relative frequency distribution (in percents). Fisher's exact test was used to detect group differences in the prevalence of AITD. Pearson's correlation coefficient r was applied to investigate the relationships between prolactin and auto-antibody levels.

Results

The medical records of 462 Caucasian prolactinoma patients (367 women and 95 men) diagnosed and followed up between 1979 and 2010 at the University Hospital, Liege, Belgium were analyzed. As the evaluation of the thyroid status is crucial for all newly diagnosed hyperprolactinemic subjects in order to exclude functional hyperprolactinemia due to non compensated primary hypothyroidism, we had a low rate of missing data in our study population (2.16%). The median prolactin (PRL) value at diagnosis of prolactinoma was 2430.5mIU/L [range: 1017–98999; IQR 1541–6858]; mean age at diagnosis was 35.96 years (range: 10.5–81.3; IQR 25.9–45.1). The mean age at study entry was 50.8 years (range: 18–99 years). Macroadenomas (tumor size range: 11–50mm) were identified in 16% (n =60) of females and 60% (n =57) of male patients.

Autoimmune thyroid diseases (AITD) were registered in 21.0% (97 pts) of all investigated subjects: 23.2% (n =85) of females and 12.6% (n =12) of males. In 51.5% (n =50; 44 women/6 men) of the patients the diagnosis of prolactinoma preceded the development of AITD with median 3 [2, 3, 4, 5, 6, 7, 8] years. Among this group 38% (n =19; 2 men/17 women) of patients had persistent hyperprolactinemia in spite of treatment. In 37.2% (n =36), both diseases were diagnosed simultaneously and only 11.3% (n =11) of patients first developed AITD.

The mean annual incidence of AITD was estimated to 24 cases/1000 prolactinoma patients (the median incidence was 16.1/1000/year). Predominant proportion of patients (80.4%; n =78) had positive autoantibodies (66.7% of them with both TPO-Ab and TGAb positive; 15.4% TPO-Ab only positive; 11.5% TGAb only positive; 6.4% TRAb positive). Diagnosis AITD in the rest 19.6% (14 with negative autoantibodies and 5 with missing data) was based on the simultaneous presence of typical ultrasound thyroid pattern and spontaneous hypothyroidism. Diffuse non homogenous hypoechogenic thyroid structure was documented in 81.4% (n =79) and nodular changes in 18.6% (n =18) of all patients with AITD. Frequencies of AITD among different age groups are presented at Table 1. As we did not have complete information about the menopausal status of all women, we divided the female group into 2 subgroups using the cut-off of 55 years (according to the definition of late-onset menopause). The prevalence of AITD as well as hypothyroidism among the older women (≥55 yrs) was higher than this in the younger group (≤54 yrs) but the difference was not statistically significant (AITD: 27.5% vs 21.3%, P =0.223; hypothyroidism: 18.8% vs 15.2%, P =0.443). Frequencies of overt hypothyroidism in females by decades are shown in Fig. 1. We did not perform such analysis in males because of the small number of patients in subgroups.



Fig. 1


Fig. 1. 

Prevalence of overt hypothyroidism in women by decades (in %). OH: overt hypothyroidism.

Zoom

Analysis of the thyroid function was performed using medical records of 404 prolactinoma patients. All subjects (n =58; 19 women/39 men; 5 with AITD/53 without AITD) with laboratory findings consistent with hypopituitarism (in spite of the severity and the number of anterior pituitary hormone deficits) were excluded from the analysis of thyroid function in order to allow a correct interpretation of TSH values. Hyperthyroidism with positive TRAb (Graves’ disease) was observed in 1.43% (n =5) of women with prolactinomas whereas none of the male patients was diagnosed with an increased thyroid function. Hypothyroidism was found in 15.6% of all patients (16.4% in females and 10.7% in males; 10.4% subclinical and 5.2% overt hypothyroidism) (Table 2). Initial hyperthyroid phase (hashitoxicosis) was documented in five (8%) of all patients with hypothyroidism. The mean daily substitutive dose of levothyroxine was 82±41.6μg [range: 25–250μg]. Euthyroid state was found in 24 subjects, 87.5% (n =21) of whom were with positive antithyroid auto-antibodies.

We did not find a correlation neither between PRL and TPO-Ab levels (Pearson's r =0.123; P =0.310) nor between PRL and TG-Ab levels (r =0.156; P =0.214).

In addition, autoimmune diseases other than thyroid were registered in 4 patients: 1 case of systemic lupus erythematosus; 1 patient with Crohn's disease, 1 woman with lymphocytic vasculitis and another one with autoimmune polyglandular syndrome including Hashimoto's thyroiditis, celiac disease and Addison's disease.

Discussion

Our cross-sectional retrospective study demonstrated a high frequency of the autoimmune thyroid diseases (AITD) in unselected population of Belgian patients with prolactinomas.

Although being the most common autoimmune disorders the prevalence of AITD among the general population is not well established [24]. Data from different epidemiological studies vary considerably depending on geographic region, age, sex, race, genetic, and environmental factors [25]. The iodine intake is considered to be a very important modulator of thyroid autoimmunity in genetically predisposed individuals. Epidemiological studies have shown that high iodine intake negatively correlates with the prevalence of hyperthyroidism, but favors the development of hypothyroidism [26, 27, 28, 29]. Experimental studies suggest that the underlying mechanism of this phenomenon is the inhibition of many thyroid processes and stimulation of follicular cell apoptosis [30].

Belgium is one of the Western European countries with well-documented mild iodine deficiency [31, 32]. Consequently, a low prevalence of AITD and especially the autoimmune hypothyroidism should be expected. In contrast, the prevalence of the spontaneous hypothyroidism (15.6%) due to AITD was significantly higher in both female and male subgroups of our cohort with prolactinomas in comparison with the general population. As there is no published Belgian population-based study, we could only compare our data with the frequency of hypothyroidism in areas with similar iodine status: Turkey (4.3%), Northern Hungary (5.0%), Poland (7.9%), Italy (3.0%) [33, 34, 35, 36]. The prevalence of anti-thyroid autoantibody positivity and spontaneous hypothyroidism in our patients was even higher than the percentages reported in regions with more than adequate iodine intake such as USA and some areas of Japan and China [37, 38, 39, 40].

One new Belgian cross-sectional retrospective study conducted at the Centre for Reproductive Medicine/University Hospital of Brussels investigated TPO-Abs positivity among 5076 consecutive young women divided in 3 categories based on their ovarian reserve (low, normal and high). Researchers found comparable percentages of positive TPO-Abs (12.1% vs 10.3% vs 9.8%; P =0.423) as well as of the frequency of hypothyroidism (4.1% vs 4.6% vs 3.8%; P =0.645) between the three groups [41].

As another important factor apart from iodine status is the genetic background (HLA, CTLA4, PNTP22, etc.), we compared our results with literature data from genetically similar to Belgium populations such as Dutch and French. According to the Nijmegen Biomedical Study, a population-based survey conducted in the eastern part of The Netherlands characterized with borderline sufficient iodine intake, primary hypothyroidism was diagnosed in 4.4% (4.0% subclinical and 0.4% overt, respectively) and positive TPOAbs were found in 8.6% of males and 18.5% of females [42]. It is well established that prevalence of hypothyroidism increases in the elderly. Another Dutch study revealed overt hypothyroidism in 7% of 558 subjects aged between 85 and 89 years [43]. According to published data from the SU.VI.MAX cross-sectional study on a large representative sample (n =11,256) of the French continental adult population, 8.1% of participants had known thyroid disease. The prevalence of newly diagnosed hypothyroidism in men was 4.2% (4.0% subclinical and 0.2% overt), in women aged from 35 to 44 yrs – 7.6% (7.2% subclinical, 0.4% overt), and older women (45–60 yrs) – 11.8% (11.1% subclinical, 0.7% overt) [44]. Among the participants of the ORCHIDÉE Study, 59.4% were diagnosed with autoimmune thyroiditis which is considered to be the leading cause of spontaneous primary hypothyroidism [45]. The prevalence of overt hypothyroidism in our female patients with prolactinomas is approximately ten times higher compared to the above-mentioned data.

In contrast to hypothyroidism, the prevalence of hyperthyroidism in our investigated patients is comparable with the literature data from community-based studies [27, 46].

Experimental studies have demonstrated that prolactin influences both humoral and cell-mediated immune responses at many levels. Based on our data, we could assume that organic hyperprolactinemia due to prolactinoma may contribute to development of autoimmune thyroid diseases in the presence of genetic predisposition. An additional argument in favor of this hypothesis is the fact that most of our AITD patients were diagnosed with autoimmune thyroid disease shortly after or simultaneously with the diagnosis of prolactinoma. In addition, substantial proportion of subjects in these two categories had documented persistent hyperprolactinemia in spite of dopamine agonist treatment.

Nevertheless, we failed to find any relationship between thyroid autoantibody and prolactin levels, but this result may not be reliable considering that this analysis was performed using a statistically small sample which consisted only of the parameters at the time of diagnosis in non treated patients in order to exclude the potential influences of either levothyroxine or dopamine agonist therapy. We should also take into consideration all main limitations of the retrospective study (risk of selection bias and unrecognized confounding variables, missing data about the family history of autoimmune diseases and smoking status, etc.), as well as the lack of appropriate control group and data from population-based study in our particular case. Finally, we should not disregard the trend toward rising incidence rates among most autoimmune disorders reported by recent reviews and meta-analyses [47]. Well-designed prospective case-control studies are needed to further investigate this topic.

In conclusion, it is difficult to establish a direct link between AITD and prolactinoma based only on epidemiological data. However, our findings raise a question about possible role of supraphysiologically increased prolactin levels in the pathogenesis and the clinical course of AITD in genetically predisposed patients with prolactinomas. As we observed increased frequency of hypothyroidism but not of hyperthyroidism, predominantly activated T-cell autoimmunity associated with organic hyperprolactinemia could be suggested. We recommend routine screening for AITD with simple thyroid tests. Except the measurement of TSH (which is obligatory to exclude functional hyperprolactinemia associated with non-compensated primary hypothyroidism), we also suggest screening for TPO-Abs and ultrasound examination in all patients diagnosed with prolactinoma.

Disclosure of interest

The authors declare that they have no competing interest.

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