Jacobs Journal of Diabetes and Endocrinology

Subclinical Hyperthyroidism Progressing to Graves’ disease After Excision of a Non-Function Pituitary Adenoma: A Case Report

*Husain Taha Radhi
Department Of Endocrinology, Salmanyia Medical Complex, Ministry Of Health, Bahrain, Bahrain, Bahrain

*Corresponding Author:
Husain Taha Radhi
Department Of Endocrinology, Salmanyia Medical Complex, Ministry Of Health, Bahrain, Bahrain, Bahrain

Published on: 2018-11-22


Non-functioning pituitary adenomas (NFPA’s) are common type of pituitary tumors. They usually presentlate with compression symptoms. Graves’ disease is an autoimmune disease affecting the thyroid hormone receptors inthe thyroid gland. The relationship between these two pathologies is extremely rare and to our knowledge, has not beendescribed in the literature yet. In this report we describe a case of a patient who was diagnosed with a NFPA and found outto have Graves’ disease after resection of the Adenoma.


Graves’ disease; Thyrotoxicosis, Pituitary Adenoma, Diabetes Insipidus

Abstract Background:

Non-functioning pituitary adenomas (NFPA’s) are common type of pituitary tumors. They usually present late with compression symptoms. Graves’ disease is an autoimmune disease affecting the thyroid hormone receptors in the thyroid gland. The relationship between these two pathologies is extremely rare and to our knowledge, has not been described in the literature yet. In this report we describe a case of a patient who was diagnosed with a NFPA and found out to have Graves’ disease after resection of the Adenoma.

Case Presentation: A 36-year-old female presented to the Gynecology clinic with amenorrhea. She also described recurrent headaches and visual symptoms. Her initial laboratory findings showed suppressed TSH with normal T4 and T3 and no associated thyroid symptoms. Her prolactin was mildly elevated. Then MRI-Brain was done for her which showed a large intrasellar mass. A diagnosis of non-functioning pituitary macro-adenoma was suspected and she had a transsphenoidal resection with histology confirming our suspicion. Since it was a complete resection, she developed hypopituitarism and was started on hormone replacement therapy. Initially, her laboratory findings were stable. Six months after, T4 was noted to be persistently elevated despite reducing and stopping levothyroxine. This, in addition to hyperthyroidism symptoms, prompted us to do thyroid scan which was consistent with Graves’s disease. She received radioactive iodine ablationand has been in remission ever since.

Conclusion: This is a rare case of Graves’s disease that developed after the excision of a Non-functioning pituitary adenoma. Up to our knowledge, no similar cases or link between those two pathologies has been described in the literature. It highlights the need of thorough history and examination with appropriate laboratory investigations of patients on exogenous thyroid hormone treatment and not to assume that the hyperthyroid status is related to medications only.

Keywords: Graves’ disease; Thyrotoxicosis, Pituitary Adenoma, Diabetes Insipidus.


Graves’ disease is an immunological disease, targeting the thyroids timulating hormone receptors in the thyroid gland [1]. It is the most common cause of hyperthyroidism [2]. Graves’ disease is also characterized by goiter, hyperthyroidism and, in25% of patients, Graves ophthalmopathy [3]. Pituitary tumors are present in up to 10 - 20% of the population, most being benign, sporadic, or familial [4]. They could be functioning or non-functioning. Clinically,Non-functioning pituitary adenomas (NFPA’s) constitute over one-third of all pituitary adenomas [5]. They do not usually cause any hormonal hyper secretion syndromes but rather present with symptoms and signs related to the mass effect of the pituitary lesion such as headaches and visual disturbances [5]. NFPA’s commonly occur during adulthood with a median age at diagnosis of 51.5 years (range 19–79 years) [6]. TSH secreting adenomas (TSHomas) are very rare and represent only 1% of all pituitary tumors [7]. Very few cases of coexistence of TSHoma with hyperthyroidism due to Graves’ disease have been reported [8]. Our case is even rarer as it describes a patient who initially presented with pressure symptoms from a non-functioning pituitary adenoma and subclinical hyperthyroidism that progressed into grave’s disease after resection of the pituitary gland. The link between a non-functioning pituitary adenoma and Graves’ disease has never been described in the literature which makes our case to our best knowledge the first of its kind, extremely rare.

Case Report

The patient was a 36-year-old female who presented to the gynaecology clinic with a 1-year history of amenorrhea. Upon further questioning she also described visual symptoms and recurrent headaches over a similar period of time. She denied other symptoms. There was no significant background medical, surgical, and social history and no regular medications. She’s a non-smoker with no alcohol intake. Her vitals were as follows: BP 125/80 mmHg, HR 78 bpm, T 37 degrees Celsius, and oxygen saturations of 99% on room air. On examination, she had no significant findings with normal neurological, cardiovascular, respiratory, and head nd neck exams. Her initial laboratory findings showed a normal full blood count, renal and liver function tests. Her hormonal panel showed the following: TSH 0.2mIU/L (RR, 0.25-4.0), T4 17.7 pmol/L (RR, 6.0-24.5), T3 5.9pmol/L (RR, 2.5-7.5), LH 1.9 IU/L (RR, 0.7-9.9), FSH 5.7 IU/L (RR, 1.8- 8.8), and Prolactin 61.3 ng/ml (RR, 3.4-24.1). The course of events are summarized in (Table 1). A pituitary tumour was suspected given the above presentation and laboratory findings. Then, MRI-brain was done which showed an intra sellar mass of 3.8 x 2.4 cm involving the pituitary gland [Figure 1].

Figure 1: Magnetic resonance scan, (A) initial MRI shows an intra sellar mass of 3.8 x 2.4 cm involving the pituitary gland, and (B)MRI post-surgical resection of the mass. She was scheduled for a transsphenoidal resection, but it was unsuccessful and she ended up getting decompression and biopsy. The histology came as pituitary adenoma [Figure 2].

Table 1. Timeline of findings and progress after initial presentation

Figure 2: Histopathological findings: Hematoxylin and eosin staining for the cells in the surgical specimen showed diffuse sheets of small round nucleated cells (A x 20), (B x 40) with amphophilic separated by thin vascular septae and variable hyaline sclerorsis in between. PAS (C) and Chro

The patient then travelled abroad to get the surgical procedure repeated which was successful. She was then started on hormone replacement therapy including thyroid hormone. A few months later, she visited our endocrinology clinic and she was noted to be in a hyperthyroid state: TSH 0.0mIU/L (RR, 0.25- 4.0), T4 36 pmol/L (RR,6.0-24.5), T3 16pmol/L (RR, 2.5-7.5).

Therefore, the levothyroxine dose was reduced as it was assumed to be secondary to it. The levels of T4 and T3 remained high despite stopping the levothyroxine. Also, she developed signs and symptoms related to hyperthyroidism including ophthalmopathy, but there was no goiter. Thyroid scan was done and it showed features suggesting Grave’s disease. The diagnosis and treatment options were then discussed with our patient and it was decided to proceed with Radioactive Iodine Ablation. She eventually became hypothyroid and was started on levothyroxine. After a few adjustments in dosages she became clinically and biochemically euthyroid. Her Grave’s disease has been in remission ever since.


We report a case of a lady who suffered from the progression of subclinical hyperthyroidism to Grave’s disease following pituitary adenoma resection. She initially presented with amenorrhea, bitemporal hemianopia, and headaches which are the classical top features of NFPA mentioned in the literature [9-10]. (Table2). Her MRI scan showed a pituitary macroadenoma which was later confirmed histologically. Her initial laboratory findings showed hyperprolactinemia of 61.3 ng/ml (RR, 3.4-24.1) which is commonly found in NFPA’s. Zhang et al reported that the prevalence of hyperprolactinemia in NFPAs is 40.2% [11]. It can sometimes be difficult to distinguish between NFPA with hyperprolactinemia and a prolactinomaas the management differs since the latter responds to medical therapy. Hong et al suggested that old age, extrasellar tumors extension with relatively low prolactin levels<100ng/ml, visual defect, and GH deficiency are considered suggestive of NFPA rather than prolactinoma in hyperprolactinaemic pituitary macroadenoma [12].

Due to the lack of hypersecretory endocrine signs and symptoms, the diagnosis of NFPA is often delayed and usually presents late as a macroadenoma [9]. Clinical manifestations are usually insidious and are represented by endocrinological symptoms, such as hypopituitarism, prolactin hypersecretion, and neurological symptoms due to mass effects similar to our case [9]. In such cases, the preferred treatment is surgical resection via the transsphenoidal route with or without adjuvant radiotherapy particularly when there is visual compromise [13]. The aim of treatment is to improve and or reverse the consequences of the pressure effects and to prevent further tumor growth. Since tumor control is not always achieved, it is advised to closely monitor for regrowth usually with annual imaging. The literature suggests 5-yearregrowth rates of 15% to 66% after surgery alone and 2% to 28% after surgery followed by adjuvant radiotherapy [13].

Table 2: Top clinical manifestations of Non-Functioning Pituitary Adenomas and Grave’s Disease.

Our patient underwent transsphenoidal resection without radiotherapy leading to pan-hypopituitarism and being placed on hormone replacement therapy. Her first visit to our clinic was six months after the surgery and she was noted to be continuously hyperthyroid despite reducing and then stopping the dose of levothyroxine. This led to the diagnosis of Graves’ disease, keeping in mind that our patient initially presented with subclinical hyperthyroidism. A case showing low serum TSH concentration with normal levels of peripheral thyroid hormones in the absence of symptoms requires further confirmation with a complete thyroid profile analysis, including assessments of serum FT4 and T3 levels, after 1–3 months. Endogenous subclinical hyperthyroidism affects approximately 1% of the general population [14]. The treatment of subclinical hyperthyroidism is controversial because the frequency of progression to overt hyperthyroidism is unknown. However, some reports indicate that approximately 50% of the cases of abnormal serum TSH levels resolve spontaneously [15]. This resolution may depend on the cause of endogenous hyperthyroidism, the initial serum TSH concentration, and the age of the patient [14]. There is little information regarding the natural history of subclinical hyperthyroidism due to Graves’ disease. A third of patients with Subclinical hyperthyroid due to Grave’s Disease will progress, a third will normalize, and the last third will remain in the Subclinical Hyperthyroid state [16]. Our patient was initially clinically euthyroid and only developed the symptoms a year after her NFPA resection. After being diagnosed with Grave’s disease, treatment options were discussed with our patient. Since this is the first episode with mild ophthalmopathy then the first line of treatment is medical therapy, Radioactive Iodine Ablation (RIA), or surgical resection [3]. There is no perfect treatment in such cases and the choice is dependent on multiple factors. She eventually decided to undergo radioiodine ablation. RAI is an effective treatment for Graves’ thyrotoxicosis, but it is associated with a failure rate of 15% and may be a risk factor for thyroid eye disease and weight gain [16]. Fortunately, RAI was successful in our patient and she has been clinically and biochemically euthyroid ever since.


We described here, for the first time, an association of progression of subclinical hyperthyroidism to Graves’ disease in a patient with hormonal supplementation for central hypothyroidism after surgery of NFPA. This case is extremely rare and a similar case hasn’t been reported in the literature yet. A thorough history and examination with appropriate laboratory investigations are important in such cases, as the events were unusual. The timing of events may suggest that there is link between the tumor resection and progression into Grave’s disease. Further studies are needed to link this association.


1 Bokhari SA, Khan PM, Akl AF.et.al. A case of severe autoimmune hepatitis associated with Graves’ disease. J Health. Spec 2016; 4:64-7.

2 Baagar K, Siddique M, Arroub S. et.al. Atypical Complications of Graves’ Disease: A Case Report and Literature Review. Case Rep Endocrinol; 2017: 6087135.

3 Bartalena L. Diagnosis and management of Graves’ disease: a global overview .Nat. Rev. Endocrinol 2013; 9: 724– 734.

4 Budan RM, Georgescu CE.Multiple Pituitary Adenomas: A Systematic Review. Front. Endocrinol. 2016; 7:1.

5 Vargas G, Gonzalez B, Ramirez C. et.al. Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas. Int J Endocrinol. 2015; 756069.

6 Andela CD, Lobatto DJ, Pereira AM. Et.al.How non-functioning pituitary adenomas can affect health-related quality of life: a conceptual model and literature review. Pituitary 2018 ;21(2):208-216.

7 Li J, Tan H, Huang J. et.al. Case report of recurrent atrial fibrillation induced by thyrotropin-secreting pituitary adenoma with Graves’ disease. Medicine 2018; 97:24.

8 Kamoun M, d’ Herbomez M, Lemaire C. et.al. Coexistence of Thyroid-Stimulating Hormone-Secreting Pituitary Adenoma and Graves’ Hyperthyroidism. Eur Thyroid J. 2014;3(1):60-64.

9 Cury ML, Fernandes JC, Machado HR. Non-functioning pituitary adenomas: clinical feature, laboratorial and imaging assessment, therapeutic management and outcome. Arq Bras Endocrinol Metab 2009;53(1):31-39.

10 Sarr A, Diédhiou D, Ndour-Mbaye M N. et.al. Graves’ Disease in Senegal: Clinical and Evolutionary Aspects. Open Journal of Internal Medicine 2016; 6: 77-82.

11 Zhang F, Huang Y, Ding C. et.al. The prevalence of hyperprolactinemia in non-functioning pituitary macroadenomas. Int J Clin Exp Med 2015;8(10):18990-18997.

12 Hong JW, Lee MK, Kim SH.et.al. Discrimination of prolactinoma from hyperprolactinemic non-functioning adenoma. Endocrine 2010;37(1):140-7.

13 Tampourlou M, Ntali G, Ahmed S. et.al. Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers. J Clin Endocrinol Metab 2017;102(6):1889–1897.

14 Poola R, Mathiason MA, Caplan RH. A retrospective study of the natural history of endogenous subclinical hyperthyroidism. WMJ 2011 ;110(6):277-80.

15 Santos P S, Pascual C E, Galofre JC.Management of Subclinical Hyperthyroidism.Int J Endocrinol Metab.2012;10(2):490-6.

16 Zhyzhneuskaya S, Addison C, Tsatlidis V. The Natural History of Subclinical Hyperthyroidism in Graves’ Disease: The Rule of Thirds. Thyroid 2016;26(6):765-9.

17 Aung ET, Zammitt NN, Dover AR.et.al. Predicting outcomes and complications following radioiodine therapy in Graves’ thyrotoxicosis. Clin Endocrinol (Oxf) 2018;6.