Open Access

Hypothyroidism With ACTH Deficiency During Pembrolizumab Therapy for Lung Cancer: Case Report and Literature Review


1Department of Thoracic Surgery, Onga Nakama Medical Association Onga Hospital, Onga-gun, Japan

2Department of Diabetes and Internal Medicine, Onga Nakama Medical Association Onga Hospital, Onga-gun, Japan

3Department of Surgery, Onga Nakama Medical Association Onga Hospital, Onga-gun, Japan

Cancer Diagnosis & Prognosis Jul-Aug; 3(4): 498-503 DOI: 10.21873/cdp.10246
Received 28 March 2023 | Revised 04 December 2023 | Accepted 07 April 2023
Corresponding author
Asato Hashinokuchi, Department of Thoracic Surgery, Onga Nakama Medical Association Onga Hospital, 1725- 2, Ooaza-Ozaki, Ongacho, Onga-gun, Fukuoka 811-4342, Japan. Tel: +81 922813810, email:


Background/Aim: Immune-checkpoint inhibitors have recently shown great promise in treating various cancers, but often cause immune-related adverse events (irAEs). Simultaneous drug-induced hypothyroidism and isolated adrenocorticotropic hormone (ACTH) deficiency are rare irAEs. This combination of irAEs is associated with paradoxical endocrine dysfunction characterized by large amounts of thyroid-stimulating hormone (TSH) and small amounts of ACTH in the anterior lobe of the pituitary. We herein report a case of hypothyroidism with isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. Case Report: Our patient was a 66-year-old man with recurrence of squamous cell lung carcinoma. Four months after chemotherapy that included pembrolizumab, the patient presented with general fatigue and laboratory tests showed high concentrations of TSH with low concentrations of free-T4. He was diagnosed with hypothyroidism and levothyroxine was prescribed. His ACTH concentration was found to be low 1 week later when he developed an acute adrenal crisis with associated hyponatraemia. We then changed his diagnosis to concurrent hypothyroidism with isolated ACTH deficiency. His condition improved after 3 weeks of administration of cortisol. Conclusion: It is difficult to diagnose a concurrent paradoxical endocrine disorder, such as hypothyroidism with isolated ACTH deficiency, as in the present case. Physicians should pay attention to symptoms and laboratory data to identify various types of endocrine disorders as irAEs.
Keywords: Hypopituitarism, hypothyroidism, immune-checkpoint inhibitors, immune-related adverse events, isolated ACTH deficiency, lung cancer

Immune-checkpoint inhibitors (ICIs), such as nivolumab, pembrolizumab and ipilimumab, have anti-tumour effects through T-cell activation and have recently shown great promise in the treatment of various cancers. Programmed death ligand-1 (PD-L1) is expressed in 35%-95% of non-small cell lung cancers and overall survival of patients with PD-L1 (tumour proportion score ≥1%) is reportedly significantly longer in patients receiving pembrolizumab than in those receiving chemotherapy without ICIs (1,2). However, ICIs can also cause various autoimmune-like responses in different organs; these are termed immune-related adverse events (irAE). Of these endocrine irAEs, thyroid dysfunction is the most common, affecting more than 10% of patients receiving ICIs (3). Care must be taken when treating such hypothyroidism because levothyroxine may lead to acute adrenal crisis when cortisol concentrations are low (4). It is standard practice to check carefully for adrenal insufficiency in patients with panhypopituitarism with low concentrations of thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH), however, unexpected paradoxical endocrine disorders such as our patient’s high concentrations of TSH and low concentrations of ACTH are more difficult to suspect and identify. Here, we describe experiencing this diagnostic pitfall through a patient with simultaneous hypothyroidism and hypopituitarism (isolated ACTH deficiency) during pembrolizumab therapy for recurrent lung cancer.

Case Report

The patient was a 66-year-old man who had undergone right upper lobectomy and lymph node dissection for squamous cell lung cancer (pathological T2N2M0 according to TNM classification 8th edition) approximately 1 year earlier. He had received adjuvant chemotherapy with four cycles of cisplatin and vinorelbine. However, 8 months after surgery, computed tomography (CT) of the chest showed multiple lung metastases in the lung fields bilaterally and mediastinal lymphadenopathy, resulting in a diagnosis of recurrence of squamous cell lung cancer. Immunohistochemical findings showed upregulated expression of programmed death ligand-1 (PD-L1) (tumour proportion 49%). He was therefore administered chemotherapy with four cycles of carboplatin, nab-paclitaxel and pembrolizumab, followed by additional cycles of pembrolizumab. Four months after commencing pembrolizumab, he presented with general fatigue. His tumours were found to be well-controlled; chest CT showing decreases in the sizes of his multiple pulmonary metastases and mediastinal lymphadenopathy. However, blood tests showed mild anaemia (haemoglobin 9.9 g/dl), hyponatraemia (potassium 129 mmol/l), hypochloraemia (chloride 95 mmol/l), and thyroid dysfunction [TSH 41.22 μIU/ml and free-T4 (FT4) 0.66 ng/dl] (Table I). We considered immune-related adverse events (irAEs) and diagnosed hypothyroidism caused by pembrolizumab. We did not suspect concurrent hypopituitarism because the TSH concentration was high and magnetic resonance imaging (MRI) showed no evidence of inflammation in the pituitary gland (Figure 1). One week after commencing levothyroxine 25mg, blood tests showed more marked hyponatraemia (Na 118 mmol/l) and simultaneous adrenal insufficiency was diagnosed (ACTH: <1.5 pg/ml and cortisol: 0.4 μg/dl). Considering that our patient had secondary adrenal insufficiency caused by levothyroxine, we diagnosed isolated hypopituitarism complicated by hypothyroidism induced by pembrolizumab (Figure 2). We administered hydrocortisone (15 mg/day) for adrenal insufficiency and his condition improved greatly over the next 2 weeks (Figure 3). Three weeks after commencing cortisol, his hyponatraemia had resolved and docetaxel hydrate was substituted for the pembrolizumab. TSH and FT4 concentrations improved slowly, returning to normal 10 months after commencing levothyroxine. He continued to receive chemotherapy with both hydrocortisone and levothyroxine for 21 months after receiving pembrolizumab. However, he died of a cerebral haemorrhage soon after ceasing chemotherapy.


We herein report a rare case of simultaneous hypothyroidism and isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. Endocrine dysfunctions are reportedly the commonest irAEs, and the reported rates of thyroid and pituitary irAEs being 13.5%-20.8% and 0.4%-3.25%, respectively (5). Hypopituitarism is classified into three categories depending on the part of the pituitary gland affected: the anterior pituitary gland (adenohypopituitarism), posterior pituitary (infundibuloneurohypopituitarism), or the whole pituitary (panhypopituitarism). Patients with adenohypopituitarism generally have decreased secretion of ACTH, TSH, growth hormone, prolactin, luteinizing hormone, and follicle stimulating hormone. However, a variant of adenohypopituitarism, namely isolated ACTH deficiency, has recently been identified. It is characterized by decreased secretion of ACTH and normal secretion of other pituitary hormones (6). The frequency of isolated ACTH deficiency as an irAE is reportedly only 0.87% (7); thus, simultaneous hypothyroidism and isolated ACTH deficiency must be extremely rare.

Twelve cases, including the present one, of hypothyroidism with isolated ACTH deficiency as irAEs have been reported (Table II) (8-18). Eight of these patients had isolated ACTH deficiency after having hypothyroidism, whereas the remaining four had both irAEs simultaneously. Notably, to the best of our knowledge there are no reported cases of hypothyroidism developing after isolated ACTH deficiency. Six of these patients had received nivolumab, five pembrolizumab, and one nivolumab and ipilimumab. The most commonly associated tumour was lung cancer (five patients) followed by melanoma (three), gastric cancer (one), kidney cancer (one), urothelial cancer (one), and breast cancer (one).

The symptoms of thyroid and pituitary irAEs are non-specific and similar, including general fatigue, appetite loss, nausea, and anorexia (5,19). In the present case, our patient presented with only general fatigue. As shown in Table II, these patients had mostly non-specific manifestations except for loss of consciousness caused by hypoglycaemia and hypotension caused by adrenal deficiency (8-18). Patients with hypothyroidism alone tend to be asymptomatic (62.5%) in Table II (8-15). In our hospital, laboratory data of TSH and FT4 is available immediately, whereas measurement of ACTH takes several days. Relying on physical examination alone may lead to overlooking co-existing irAEs. As shown in Table II, 10/12 (83.3%) patients with hypothyroidism and isolated ACTH deficiency had hyponatraemia and hypoglycaemia (8-18). Thus, laboratory tests may be useful for diagnosing concurrent irAEs in asymptomatic patients receiving ICIs.

MRI findings were normal in almost all reported patients (92%) with hypothyroidism and isolated ACTH deficiency (Table ΙΙ). A systematic review investigating isolated ACTH deficiency as an irAE revealed that MRI findings were normal in 93% (n=60) of the patients (7). However, the pituitary was enlarged in almost all patients with autoimmune panhypopituitarism (20). Importantly, physicians should remember that endocrine dysfunction may be present in patients whose pituitary glands appear normal on MRI.

Recent reports have indicated that age (<60 years), high body mass index, sarcopenia and history of autoimmune disease are clinical risk factors for irAEs (21). In addition, high neutrophil-lymphocyte ratio, absolute monocyte count, absolute platelet count and higher baseline albumin have also been reported as the predictive biomarkers (21,22). Kurimoto et al. reported that early change of serum thyroglobulin, thyroid auto-antibodies and cytokine level were associated with development of thyroid-related irAEs (23). These studies suggested that these biomarkers may detect the irAEs. Further studies for predicting irAEs are necessary.

In the present case, we experienced a paradoxical endocrine dysfunction with high TSH and low ACTH level, although these hormones are secreted in the anterior lobe of the pituitary (Figure 2). This pattern of endocrine dysfunction may increase because the use of ICIs has increased in various cancers, and patients with multiple irAEs were reported to comprise 9.0% of patients receiving anti-PD-L1 therapy (24). Therefore, it is important to suspect the possibility of paradoxical endocrine dysfunction and evaluate comprehensively various types of hormones to follow up the treatment by ICIs.


This report has presented a rare case of simultaneous drug-induced hypothyroidism and hypopituitarism characterized by isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. Hypothyroidism with isolated ACTH deficiency as an irAE is very rare; however, it is important to be careful about the possibility of concurrent isolated ACTH deficiency even if the level of TSH is high because the administration of levothyroxine prior to cortisol can cause acute adrenal crisis in the presence of irAEs. In addition, the comprehensive follow-up of hormone levels is useful for the diagnosis of irAEs; careful attention to the symptoms and laboratory data might prevent diagnostic pitfalls relating to various types of irAEs during treatment with ICIs.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to this study.

Authors’ Contributions

Asato Hashinokuchi searched the literature and wrote the manuscript. Akira Haro provided direct patient care, searched the literature, and edited the manuscript. All Authors read and approved the final manuscript.


The Authors would like to thank Dr. Tomoyuki Hida for instructing us in the interpretation of MRI images and Dr. Trish Reynolds, MBBS, FRACP, from Edanz ( for editing a draft of this manuscript.


1 Tang S Qin C Hu H Liu T He Y Guo H Yan H Zhang J Tang S & Zhou H Immune checkpoint inhibitors in non-small cell lung cancer: Progress, challenges, and prospects. Cells. 11(3) 320 2022. PMID: 35159131. DOI: 10.3390/cells11030320
2 Mok TSK Wu YL Kudaba I Kowalski DM Cho BC Turna HZ Castro G Jr Srimuninnimit V Laktionov KK Bondarenko I Kubota K Lubiniecki GM Zhang J Kush D Lopes G & KEYNOTE-042 Investigators Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 393(10183) 1819 - 1830 2019. PMID: 30955977. DOI: 10.1016/S0140-6736(18)32409-7
3 Muir CA Menzies AM Clifton-Bligh R & Tsang VHM Thyroid toxicity following immune checkpoint inhibitor treatment in advanced cancer. Thyroid. 30(10) 1458 - 1469 2020. PMID: 32264785. DOI: 10.1089/thy.2020.0032
4 Jonklaas J Bianco AC Bauer AJ Burman KD Cappola AR Celi FS Cooper DS Kim BW Peeters RP Rosenthal MS Sawka AM & American Thyroid Association Task Force on Thyroid Hormone Replacement Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 24(12) 1670 - 1751 2014. PMID: 25266247. DOI: 10.1089/thy.2014.0028
5 Yamauchi I Taura D Hakata T Fujita H Okamoto K Ueda Y Fujii T & Inagaki N Clinical features and thyroid dysfunction in adverse events involving the pituitary gland during PD-1 blockade therapy. Clin Endocrinol (Oxf). 94(2) 258 - 268 2021. PMID: 33037658. DOI: 10.1111/cen.14349
6 Yamamoto M Iguchi G Bando H Kanie K Hidaka-Takeno R Fukuoka H & Takahashi Y Autoimmune pituitary disease: New concepts with clinical implications. Endocr Rev. 41(2) bnz003 2020. PMID: 31513261. DOI: 10.1210/endrev/bnz003
7 Iglesias P Sánchez JC & Díez JJ Isolated ACTH deficiency induced by cancer immunotherapy: a systematic review. Pituitary. 24(4) 630 - 643 2021. PMID: 33761049. DOI: 10.1007/s11102-021-01141-8
8 Kastrisiou M Kostadima FL Kefas A Zarkavelis G Kapodistrias N Ntouvelis E Petrakis D Papadaki A Vassou A & Pentheroudakis G Nivolumab-induced hypothyroidism and selective pituitary insufficiency in a patient with lung adenocarcinoma: a case report and review of the literature. ESMO Open. 2(4) e000217 2017. PMID: 29067215. DOI: 10.1136/esmoopen-2017-000217
9 Ariyasu H Inaba H Ota T Yamaoka H Furukawa Y Iwakura H Doi N Yamamoto Y & Akamizu T Thyrotoxicosis and adrenocortical hormone deficiency during immune-checkpoint inhibitor treatment for malignant melanoma. In Vivo. 32(2) 345 - 351 2018. PMID: 29475919. DOI: 10.21873/invivo.11244
10 Martins Machado C Almeida Santos L Barroso A & Oliveira MJ Nivolumab-induced hypothyroidism followed by isolated ACTH deficiency. BMJ Case Rep. 12(8) e231236 2019. PMID: 31466960. DOI: 10.1136/bcr-2019-231236
11 Takeno A Yamamoto M Morita M Tanaka S Kanazawa I Yamauchi M Kaneko S & Sugimoto T Late-onset isolated adrenocorticotropic hormone deficiency caused by nivolumab: a case report. BMC Endocr Disord. 19(1) 25 2019. PMID: 30782163. DOI: 10.1186/s12902-019-0335-x
12 Ohara N Kobayashi M Ohashi K Ito R Ikeda Y Kawaguchi G Yoneoka Y Hasegawa G & Takada T Isolated adrenocorticotropic hormone deficiency and thyroiditis associated with nivolumab therapy in a patient with advanced lung adenocarcinoma: a case report and review of the literature. J Med Case Rep. 13(1) 88 2019. PMID: 30909965. DOI: 10.1186/s13256-019-2002-2
13 Yamagata S Kageyama K Takayasu S Asari Y Makita K Terui K & Daimon M Progression of hypopituitarism and hypothyroidism after treatment with pembrolizumab in a patient with adrenal metastasis from non-small-cell lung cancer. Intern Med. 58(24) 3557 - 3562 2019. PMID: 31462588. DOI: 10.2169/internalmedicine.3008-19
14 Zeng MF Chen LL Ye HY Gong W Zhou LN Li YM & Zhao XL Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review. Medicine (Baltimore). 96(44) e8426 2017. PMID: 29095280. DOI: 10.1097/MD.0000000000008426
15 Doodnauth AV Klar M Mulatu YS Malik ZR Patel KH & McFarlane SI Pembrolizumab-induced hypophysitis with isolated adrenocorticotropic hormone (ACTH) deficiency: a rare immune-mediated adverse event. Cureus. 13(6) e15465 2021. PMID: 34123679. DOI: 10.7759/cureus.15465
16 Takebayashi K Ujiie A Kubo M Furukawa S Yamauchi M Shinozaki H Suzuki T Naruse R Hara K Tsuchiya T & Inukai T Isolated adrenocorticotropic hormone deficiency and severe hypercalcemia after destructive thyroiditis in a patient on nivolumab therapy with a malignant melanoma. J Clin Med Res. 10(4) 358 - 362 2018. PMID: 29511426. DOI: 10.14740/jocmr3257w
17 Oristrell G Bañeras J Ros J & Muñoz E Cardiac tamponade and adrenal insufficiency due to pembrolizumab: a case report. Eur Heart J Case Rep. 2(2) yty038 2018. PMID: 31020118. DOI: 10.1093/ehjcr/yty038
18 Sasaki K Kobayashi S Kudo M Sugimoto M Takahashi S Nakamura Y Kawazoe A Shitara K Kinoshita T & Gotohda N Hypothyroidism and hypopituitarism as immune-related adverse events due to lenvatinib plus pembrolizumab therapy in the immediate postoperative period after laparoscopic hepatectomy for liver metastases from gastric cancer: a case report. Surg Case Rep. 7(1) 267 2021. PMID: 34928436. DOI: 10.1186/s40792-021-01346-w
19 Arima H Iwama S Inaba H Ariyasu H Makita N Otsuki M Kageyama K Imagawa A & Akamizu T Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society. Endocr J. 66(7) 581 - 586 2019. PMID: 31243183. DOI: 10.1507/endocrj.EJ19-0163
20 Faje A Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary. 19(1) 82 - 92 2016. PMID: 26186958. DOI: 10.1007/s11102-015-0671-4
21 Chennamadhavuni A Abushahin L Jin N Presley CJ & Manne A Risk factors and biomarkers for immune-related adverse events: a practical guide to identifying high-risk patients and rechallenging immune checkpoint inhibitors. Front Immunol. 13 779691 2022. PMID: 35558065. DOI: 10.3389/fimmu.2022.779691
22 Michailidou D Khaki AR Morelli MP Diamantopoulos L Singh N & Grivas P Association of blood biomarkers and autoimmunity with immune related adverse events in patients with cancer treated with immune checkpoint inhibitors. Sci Rep. 11(1) 9029 2021. PMID: 33907229. DOI: 10.1038/s41598-021-88307-3
23 Kurimoto C Inaba H Ariyasu H Iwakura H Ueda Y Uraki S Takeshima K Furukawa Y Morita S Yamamoto Y Yamashita S Katsuda M Hayata A Akamatsu H Jinnin M Hara I Yamaue H & Akamizu T Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors. Cancer Sci. 111(5) 1468 - 1477 2020. PMID: 32086984. DOI: 10.1111/cas.14363
24 Shankar B Zhang J Naqash AR Forde PM Feliciano JL Marrone KA Ettinger DS Hann CL Brahmer JR Ricciuti B Owen D Toi Y Walker P Otterson GA Patel SH Sugawara S & Naidoo J Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol. 6(12) 1952 - 1956 2020. PMID: 33119034. DOI: 10.1001/jamaoncol.2020.5012