Empty sella syndrome (ESS) is an entity in which the sella turcica is filled with cerebrospinal fluid via subarachnoid space herniation, due to compression of the pituitary tissue upto sellar base and walls (1,2). ESS may cause single or more than one pituitary hormone deficiencies at different levels (3). ESS is classified as primary and secondary ESS (4). Secondary ESS may occur due to radiotherapy, surgery, vascular, infective, traumatic, and autoimmune diseases in addition to some causes, such as spontaneously regressed pituitary adenomas or adenomas regressed after medical treatment (4). Primary ESS is a condition which develops without the causes mentioned above and is classified as idiopathic or primary ESS. Some studies proposed that different secondary causes might be present in patients who are accepted as having primary ESS (5). However, if all possible etiologies are ruled out carefully, the frequency of ESS cases that are defined as “idiopathic” may decrease (5). In the present study, we investigated if there was an association between Hashimoto’s thyroiditis (HT) and ESS.
We evaluated magnetic resonance imaging (MRI) results of a total of 120 patients. 70 patients who were referred to our pituitary diseases outpatient clinic between October 2014 and March 2015 and were diagnosed with primary ESS according to their cranial or pituitary MRI, history and physical examination results, and 50 patients with primary ESS who were enrolled in our previous study (3) were included in the study. All MRI’s of the patients were re-evaluated by an experienced radiologist to confirm ESS diagnosis. Patients with a history of congenital or acquired hypothalamic-pituitary diseases, previous pituitary surgery or radiotherapy, a history of head trauma, medical treatment for pituitary adenomas, patients with a prolactin levels higher than 100 ng/mL (in whom the presence of a prolactinoma could not be ruled out), patients who was diagnosed with Sheehan’s syndrome, and patients with primary adrenal or gonadal insufficiency were not included in the study. A total of 81 patients with the diagnosis of primary ESS were included in the study. Anterior pituitary deficiency and possible HT were evaluated by physical examination, ultrasonography (USG), and biochemical analysis.
The anatomical integrity of the hypothalamo-pituitary region of all of the subjects was evaluated by MRI. All MRI’s of the subjects were evaluated and/or revised by an experienced radiologist who was blind to the laboratory data and clinical condition of the subjects. The diagnosis of primary ESS was considered in the presence of intrasellar cerebrospinal fluid with a thinned pituitary gland flattened against the sellar floor (1). All MRIs were performed by means of a 1.5 Tesla superconducting magnet (Siemens Avanto, Siemens, Erlangen, Germany) with multiple sagittal and coronal planes on T1 sequences with/without gadolinium. All USG examinations of the thyroid were performed by the same radiologist. A color Doppler USG device (Toshiba, Aplio XV, Tokyo, Japan) equipped with a 7- to 14-MHz wide-band linear transducer was used. The USG criteria suggesting HT were diffuse hypoechoic enlargement, patchy ill-defined hypoechoic areas separated by echogenic fibrous septa, and micro nodular pattern involving the whole gland (6,7).
Venous fasting blood samples were obtained from each patient in the morning between 08:00 a.m. and 09:00 a.m. The samples were studied without any delay for serum thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), anti thyroid peroxidase (antiTPO), anti thyroglobulin (antiTG), prolactin, follicle stimulating hormone (FSH), luteinizing hormone (LH), cortisol and 17 β estradiol levels. Serum TSH, fT3, fT4, antiTPO, antiTG, prolactin, FSH, LH, cortisol, and 17 β estradiol levels were assessed by electrochemiluminescence immunoassay method using cobas immunoassay analyzers (Roche Diagnostics GmbH, Mannheim, Germany); and serum growth hormone, insulin-like growth factor 1, adrenocorticotropic hormone and total testosterone levels were assessed by Immulite 2000 assay (Siemens AG, Munich, Germany). HT was diagnosed if the patients had antiTPO >35 IU/mL and/or antiTG >115 IU/mL and USG results consistent with HT. In addition to the above diagnostic criteria, patients were diagnosed with hypothyroid HT if their TSH levels were >4.5 uIU/mL. Patients were diagnosed as having central hypothyroidism if TSH values were within the normal reference limits or <0.27 uIU/mL in addition to fT4<0.8 ng/dL and/or fT3<1.64 pg/mL. Patients with and without HT were compared in terms of hypertension, diabetes mellitus (DM), age, height, body weight, and body mass index (BMI).
Statistical analysis was performed by using SPSS (Statistical Package for Social Sciences for Windows, release 22.0.0 standard version; SPSS Inc, NY, USA). Nominal data were presented as percentages and numeric data were presented as mean ± standard deviation. Patients with and without HT were compared in terms of age, height, weight, and BMI, by using two-sample t-test. Gender, DM, and hypertension were compared between patients with and without HT by chi-square test. The level of significance was accepted as p<0.05.
In the present study, thyroid disease was diagnosed in 34 out of 81 (42%) patients in whom 18 (22.2%) had HT and 16 (19.8%) had central hypothyroidism (Table 1). In patients with HT, 11 (13.6%) had hypothyroidism and 7 (8.6%) were euthyroid (Table 1). Ten patients with HT (55.5%) were newly diagnosed and 8 (44.5%) were previously diagnosed. No significant difference was determined in terms of age, height, BMI, gender and hypertension between primary ESS patients with and without HT (p=0.99, p=0.27, p=0.11, p=0.93 and p=0.52, respectively). Although the frequency of DM was higher in HT patients, no statistically significant difference was determined (p=0.08). HT was observed in none of primary ESS patients with central hypothyroidism. The patient characteristics for those with primary ESS and HT and their descriptive statistical data are presented in Tables 2 and 3, respectively. Among primary ESS patients, 12 (14.8%) had hyperprolactinemia; 16 (19.7%) had central hypothyroidism, 22 (27.1%) had gonadotropin deficiency; 20 (24.6%) had GH deficiency, and 6 (7.4%) had cortisol deficiency. The diagnosis of different anterior pituitary hormone deficiencies was performed according to the relevant guidelines.
Different etiologies may be present among patients diagnosed with primary ESS (5). García-Centeno et al. (8) reported HT frequency as 26.7% among primary ESS patients (9). In the present study, the frequency of HT was 22.2% among primary ESS patients. This ratio was higher than HT prevalence (0.3-1.2%) in the general population (9,10,11,12,13). These results show that there is a relationship between HT and primary ESS.
Studies suggested an association between LH and autoimmune thyroiditis (AT) because of the similar pathological processes between LH and AT (14,15,16,17,18,19,20). It has been shown that the anti-pituitary antibody positivity rate was between 10% and 20% in HT (15,21,22). Manetti et al. (15) reported that 11.4% of 961 patients with autoimmune thyroid diseases were positive for anti-pituitary antibodies and ESS developed in approximately 10% of LH cases (23,24). LH develops due to immune mediated chronic inflammation of the pituitary gland. LH is the potential cause of idiopathic ESS because of subsequent atrophy and fibrosis following increase in pituitary gland size (23). It is quite difficult to diagnose LH. Clinical, laboratory and imaging studies are used to diagnose LH. However, none of these diagnostic methods are specific for the diagnosis of LH (23). Since it is not always possible to perform a biopsy of the pituitary gland in all suspected cases with LH or to measure anti-pituitary antibody levels, the diagnosis is generally based on exclusion of other diseases of the pituitary gland (25). Moreover, the sensitivity (20-30%) of the anti-pituitary antibody is limited in LH (21,26,27,28). As a result, AT or HT might accompany LH development, and since the diagnosis of LH is difficult, it could not be diagnosed most of the time; the condition manifest finally itself as ESS (24). Anti-pituitary antibody positivity has been determined in 22-42% of cases of primary ESS (23,28). In our study, some of the ESS cases may have been developed due to LH and LH may has accompanied HT. LH and HT may be coexisting diseases with different onset or/and progression times, but at the end, both may result in atrophy of their originating glands. Finally, LH may result in reduction of the size of the pituitary parenchyma and progress to ESS and hypofunction of the thyroid gland.
It has also been reported that ESS might develop in primary hypothyroidism (29,30). This condition is thought to be due to regression of secondary pituitary hyperplasia developing secondary to peripheral zone gland deficiency after starting levothyroxine treatment (29,30). There are case reports showing that ESS may develop after the increase of pituitary size related to primary hypothyroidism, and subsequent regression of pituitary size after levothyroxine treatment (31,32). Moreover, development of LH has been reported in patients with malignant melanoma after treatment with an anti cytotoxic T-lymphocyte associated protein-4 antibody ipilimumab (33,34), however, none of the participants in this study received such a treatment. The limitation of our study is that we could not measure anti-pituitary antibody levels. However, current diagnostic methods have limited clinical value for determination of anti-pituitary antibodies. It has been reported that sensitivity of anti-pituitary antibodies for the diagnosis of LH was between 20% and 70% (21,26,27,28).
In conclusion, as it is difficult to diagnose LH and LH, diagnosis may be often missed and final outcome may manifests as ESS. Nevertheless, LH may be an autoimmune process accompanying HT. LH may coexist with HT and may be the cause of some of the primary ESS cases. Therefore, it is recommended that the presence of HT should be investigated in patients with primary ESS. Further studies investigating anti-pituitary antibody in patients with primary ESS are needed to further declare this relationship.
Ethics Committee Approval: The study was approved by the Ethics Committee of Şişli Etfal Training and Research Hospital, Informed Consent: The concent form was filled out by all participants of this study.
Peer-review: External and Internal peer-reviewed.
Surgical and Medical Practices: İdris Kuzu, Sayid Shafi Zuhur, Concept: İdris Kuzu, Design: İdris Kuzu, Sayid Shafi Zuhur, Data Collection or Processing: Feyza Yener Öztürk, Yüksel Altuntaş, Analysis or Interpretation: İdris Kuzu, Literature Search: Alper Özel, David Ojalvo, Writing: İdris Kuzu.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
1. De Marinis L, Bonadonna S, Bianchi A, Maira G, Giustina A. Primary empty sella. J Clin Endocrinol Metab 2005;90:5471-5477.
2. McLachlan MSF, Williams ED, Doyle FH. Applied anatomy of the pituitary gland and fossa. A radiological and histopathological study based on 50 necropsies. Br J Radiol 1968;41:490-782.
3. Zuhur SS, Kuzu I, Ozturk FY, Uysal E, Altuntas Y. Anterior pituitary hormone deficiency in subjects with total and partial primary empty sella: do all cases need endocrinological evaluation? Turk Neurosurg 2014;24:374-779.
4. Akiyama Y, Yamasaki T, Kagawa T, Moritake K. Empty sella syndrome. Nihon Rinsho 1993;51:2731-2736.
5. Jara-Albarrán A, Bayort J, De Juan M, Benito C. Spontaneous partial empty sella. A study of 41 cases. Exp Clin Endocrinol 1984;83:63-72.
6. Solbiati L, Livraghi T, Ballarati E, Ierace T, Crespi L. Thyroid gland. In: Solbiati L, Rizzato G, editors. Ultrasound of superficial structures. Edinburgh: Churchill Livingstone; 1995. p. 49-85.
7. Yeh HC, Futterweit W, Gilbert P. Micronodulation: ultrasonographic sign of Hashimoto thyroiditis. J Ultrasound Med 1996;15:813-819.
8. García-Centeno R, Suárez-Llanos JP, Fernández-Fernández E, Andía-Melero V, Sánchez P, Jara-Albarrán A. Empty sella and primary autoimmune hypothyroidism. Clin Exp Med 2010;10:129-134.
9. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499.
10. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-534.
11. Jaume JC: Endocrine autoimmunity. In Greenspan’s Basic & Clinical Endocrinology. Edited by: Gardner DG, Shoback DM. New York: McGraw-Hill Medical 2007;59-79.
12. Weetman AP: Thyroid disease. In The Autoimmune Disease. Edited by: Rose NR, Mackay IR. Elsevier 2006:467-482.
13. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T, Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7:481-493.
14. Barbaro D, Loni G. Lymphocytic hypophysitis and autoimmune thyroid disease. J Endocrinol Invest 2000;23:339-340.
15. Manetti L, Lupi I, Morselli LL, Albertini S, Cosottini M, Grasso L, Genovesi M, Pinna G, Mariotti S, Bogazzi F, Bartalena L, Martino E. Prevalence and functional significance of antipituitary antibodies in patients with autoimmune and non-autoimmune thyroid diseases. J Clin Endocrinol Metab 2007;92:2176-2181.
16. De Rosa G, Della Casa S, Corsello SM, Cecchini L, Callà C. Autoimmune polyglandular syndrome, primary empty sella, and acute lymphocytic leukaemia. Clin Endocrinol (Oxf) 1987;27:535–543.
17. Goudie RB, Pinkerton PH. Anterior hypophysitis and Hashimoto’s disease in a young woman. J Pathol Bacteriol 1962;83:584-585.
18. Ozawa Y, Shishiba Y. Recovery from lymphocytic hypophysitis associated with painless thyroiditis: clinical implications of circulating antipituitary antibodies. Acta Endocrinol (Copenh) 1993;128:493-498.
19. Paja M, Estrada J, Ojeda A, Ramón y Cajal S, García-Uría J, Lucas T. Lymphocytic hypophysitis causing hypopituitarism and diabetes insipidus, and associated with autoimmune thyroiditis, in a non-pregnant woman. Postgrad Med J 1994;70:220-224.
20. Hashimoto K, Takao T, Makino S. Lymphocytic adenohypophysitis and lymphocytic infundibuloneurohypophysitis. Endocr J 1997;44:1-10.
21. Takao T, Nanamiya W, Matsumoto R, Asaba K, Okabayashi T, Hashimoto K. Antipituitary antibodies in patients with lymphocytic hypophysitis. Horm Res 2001;55:288-292.
22. Milosevi? M, Stojanovi? M, Nesovi? M. Primary hypothyroidism associated with empty sella turcica and hypopituitarism. Med Pregl 2005;58:410-413.
23. Caturegli P, Lupi I, Landek-Salgado M, Kimura H, Rose NR. Pituitary autoimmunity: 30 years later. Autoimmun Rev 2008;7:631-637.
24. Karaca Z, Tanriverdi F, Unluhizarci K, Kelestimur F, Donmez H. Empty sella may be the final outcome in lymphocytic hypophysitis. Endocr Res. 2009;34:10-17.
25. Rivera JA. Lymphocytic hypophysitis: disease spectrum and approach to diagnosis and therapy. Pituitary 2006;9:35-45.
26. Moya Chimenti E, Alvarez Doforno R, Villaroel Bajo A, Frutos R, Pallardo Sánchez LF, Alvarez Escolá C. Antipituitary antibodies in patients with suspected autoimmune hypophysitis. Endocrinol Nutr. 2010;57:160-164.
27. Keda YM, Krjukova IV, Ilovaiskaia IA, Morozova MS, Fofanova OV, Babarina MB, Marova EI, Pankov YA, Kandror VI. Antibodies to pituitary surface antigens during various pituitary disease states. J Endocrinol. 2002;175:417-423.
28. Mau M, Phillips TM, Ratner RE. Presence of anti-pituitary hormone antibodies in patients with empty sella syndrome and pituitary tumours. Clin Endocrinol. 1993;38:495.
29. Jawadi MH, Ballonoff LB, Stears JC, Katz FH. Primary hypothyroidism and pituitary enlargement. Radiological evidence of pituitary regression. Arch Intern Med 1978;138:1555-1557.
30. Plehwe WE, Fabinyi GC. Anterior pituitary hyperplasia due to primary autoimmune hypothyroidism. J Clin Neurosci 2003;10:217-218.
31. Kelestimur F, Selçuklu A, Ozcan N. Empty sella developing during thyroxine therapy in a patient with primary hypothyroidism and hyperprolactinaemia. Postgrad Med J 1992;68:589-591.
32. Luboshitzky R, Barzilai D. Primary empty sella syndrome and hypopituitarism associated with primary hypothyroidism. J Endocrinol Invest 1981;4:213-216.
33. Marlier J, Cocquyt V, Brochez L, Van Belle S, Kruse V. Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports. Endocrine 2014;47:878-883.
34. Kaehler KC, Egberts F, Lorigan P, Hauschild A. Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient. Melanoma Res 2009;19:333-334.