COVID-19 vaccines have resulted in a remarkable reduction in both the morbidity and mortality associated with COVID-19. However, there are reports of endocrine rare clinical conditions linked to COVID-19 vaccination. In this report, we present a case of hypophysitis following COVID-19 vaccination and review the literature on this condition. This case involved a 72-year-old male with type 1 diabetes who experienced symptoms such as vomiting, appetite loss, and headaches following his fifth COVID-19 vaccine dose. He was diagnosed with secondary adrenal insufficiency; subsequent assessment revealed an enlarged pituitary gland. Unlike previous cases, our patient has partial recovery from pituitary insufficiency, and his pituitary function gradually improved over time. Anti-pituitary antibodies (APAs) against corticotrophs, thyrotrophs, gonadotrophs, and folliculo stellate cells (FSCs) were detected in serum samples taken 3 months after onset. Hypophysitis after COVID-19 vaccination is a rare clinical condition, with only eight cases reported by the end of 2023, most occurring after the initial or second vaccination. Symptoms of hypophysitis after COVID-19 vaccination are similar to those of classic pituitary dysfunction. Pituitary insufficiency is persistent, with five of the above eight patients presenting posterior pituitary dysfunction and three patients presenting only anterior pituitary dysfunction. Two of those eight patients had autoimmune diseases. Our case suggests a potential link between acquired immunity, APA production, and pituitary damage. To elucidate the etiology of hypophysitis associated with COVID-19 vaccination, detailed investigation of patients with nonspecific symptoms after vaccination against COVID-19 is necessary.

COVID-19, an illness stemming from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has garnered widespread global attention owing to its sudden onset, rapid dissemination, and high mortality rate. To counteract the pandemic, diverse COVID-19 vaccines have been developed, including mRNA-based vaccines, viral vector vaccines, and inactivated and protein subunit vaccines. The implementation of these vaccines has resulted in a remarkable reduction in both the morbidity and mortality associated with COVID-19. However, there have been infrequent reports of immune-related adverse effects potentially associated with COVID-19 vaccines [1], including acute myocarditis, nephrotic syndrome, and endocrine disorders [2-4].

Since the initiation of vaccination campaigns, the primary endocrinopathies linked to COVID-19 vaccination involve thyroiditis and type 1 diabetes [5]. Additionally, pituitary dysfunction may develop as a rare clinical condition post-vaccination, with only eight previous cases reported by the end of 2023 [4, 6-12]. Notably, there are only two reports of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) associated with hypophysitis, including our case. Once functional impairment manifests, it is reported to be a permanent condition [4]. Regarding the etiology of hypophysitis, it is assumed that an autoimmune reaction exists in the background, but the details remain unclear. Of note, previous reports have made no mention of anti-pituitary antibodies (APAs) in relation to hypophysitis after COVID-19 vaccination.

Herein, we report a case of hypophysitis with secondary adrenal insufficiency after COVID-19 vaccination. Unlike previous reports, our patient had partial recovery from pituitary insufficiency. Moreover, this is the first report of hypophysitis after COVID-19 vaccination where the existence of APAs was confirmed in the patient’s serum.

A 72-year-old male, diagnosed with type 1 diabetes at approximately 40 years of age, experienced recurrent vomiting the day after his fifth BNT162b2 SARS-Cov-2 mRNA vaccine (Pfizer/BioNTech) administration. Subsequently, he progressively manifested symptoms of appetite loss, headaches, and dizziness, coupled with difficulty walking. Consequently, he sought medical attention and presented at our hospital 7 days post-vaccination. At the time of assessment, the patient’s height measured 158 cm, and his weight stood at 53 kg. Vital signs indicated a heart rate of 67 beats per minute, with a blood pressure reading of 173/87 mmHg. Physical examination identified slight disorientation but revealed no other discernible deficits. Although laboratory analyses revealed hyponatremia and increased urinary sodium excretion, the attending physicians did not diagnose adrenal insufficiency or subclinical hypothyroidism as the cause of the hyponatremia at that time (Table 1; left column). Inappropriate secretion of antidiuretic hormone caused by nausea and repeated vomiting was considered a possible cause of the hyponatremia. Implementing interventions such as salt supplementation and fluid restriction led to normalization of the patient’s serum sodium levels (134 mmol/L) and subsequent alleviation of symptoms, culminating in his discharge from the hospital.

The patient again sought medical attention 17 days subsequent to receiving his fifth COVID-19 vaccination, reporting a recurrence of nausea and vomiting. Subsequent laboratory assessment revealed hyponatremia, hypoglycemia, and notably diminished plasma ACTH and serum cortisol levels (Table 1; right column). He was diagnosed with secondary adrenal insufficiency and received intravenous administrations of hydrocortisone at 200 mg on day 18, 150 mg on day 19, and 100 mg on day 20. After that, he received oral hydrocortisone at a dose of 50 mg per day, with gradual tapering to 10 mg per day over 10 days. An enlarged pituitary gland was observed on magnetic resonance imaging (MRI) even after administration of hydrocortisone (Fig. 1A and 1B). The horizontal diameter and height of the pituitary gland were 8.15 mm and 6.63 mm, respectively. Posterior lobe hyperintensity was identified on T1-weighted non-contrast MRI (Fig. 1A). To evaluate pituitary function, a comprehensive corticotropin-releasing hormone (CRH)-thyrotropin-releasing hormone (TRH)-gonadotropin-releasing hormone (GnRH) challenge test was conducted 24 days after the fifth vaccination (Fig. 2; solid line). The results indicated that the patient’s ACTH response to CRH was approximately within the normal range, but cortisol exhibited a weak responsiveness to ACTH elevation. Regarding HPT (Hypothalamic-Pituitary-Thyroid) axis, basal thyroid-stimulating hormone (TSH) and free triiodothyronine (FT3) levels in TRH stimulation test were below normal range, indicating secondary hypothyroidism. In addition, the responses of TSH and FT3 to TRH were slightly reduced. Regarding HPG (Hypothalamic-Pituitary-Gonadal) axis, testosterone levels were within the normal range at 2.48 ng/mL, and basal luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels as well were also within normal range. The prolactin (PRL) response to TRH was normal. A rapid ACTH stimulation test performed 26 days after vaccination showed a normal cortisol response (data not shown). Additionally, an insulin tolerance test conducted on day 27 post-vaccination exhibited nearly normal ACTH and cortisol responses (Fig. 3). A growth hormone releasing peptide 2 loading test demonstrated a normal response of growth hormone (Fig. 2H). On day 28, his 24-hour urine cortisol level was 33.8 mcg per day. Despite an observed improvement in the ACTH-cortisol axis over time, cautious supplementation with small amounts of hydrocortisone was maintained for safety reasons. Throughout the follow-up period, the patient reported no complaints of polyuria or dry mouth, and his daily urine output was approximately 1,300 to 1,500 mL.

Fig. 1

Pituitary (MRI)

A: T1-weighed pituitary magnetic resonance imaging (MRI) performed 17 days after the patient received a fifth COVID-19 vaccination. B: T1-weighed gadolinium-enhanced pituitary MRI performed 17 days after the fifth COVID-19 vaccination. C: T1-weighed pituitary MRI performed 6 months after the fifth COVID-19 vaccination. D: T1-weighed gadolinium-enhanced pituitary MRI performed 6 months after the fifth COVID-19 vaccination.

Fig. 2

Pituitary stimulation test

A to G present the results after injection with comprehensive corticotropin releasing hormone (CRH; 100 mcg, iv), thyrotropin releasing hormone (TRH; 200 mcg, iv), and gonadotropin releasing hormone (GnRH; 100 mcg, iv).

Solid and dotted lines show the results 24 days and 6 months after vaccination, respectively. H represents the results after injection with growth hormone releasing peptide 2 (GHRP-2; 100 mcg, iv), which was performed only 25 days after vaccination.

Fig. 3

Insulin tolerance test

A and B present the results after insulin injection (0.05 unit/kg body weight iv).

Six months later, an extensive re-assessment was undertaken, incorporating pituitary MRI and pituitary stimulation tests conducted 7 days post-discontinuation of hydrocortisone supplementation. Gadolinium-enhanced MRI images indicated a notable reduction in the size of the pituitary gland and stalk (Fig. 1C and 1D). The horizontal diameter and height of the pituitary gland were 7.95 mm and 4.23 mm, respectively. It was established that both basal and reactive secretions of anterior pituitary hormones were within the normal range (Fig. 2; dashed line). Nonetheless, the cortisol response to increased ACTH exhibited mild weakness, signifying that the patient’s ACTH-cortisol axis remained mildly aberrant. On the basis of these results, the patient continues to take 10 mg of hydrocortisone per day.

APAs, assessed via immunofluorescence (IF), serve as a surrogate marker indicating the presence of autoimmunity against pituitary glands [13, 14]. Measurement of APAs was conducted using serum samples taken 17 days and 3 months after the fifth vaccination. Human pituitary glands were obtained from the autopsy laboratory of Nagoya University Hospital. The primary and secondary antibodies are listed below, and details of the method used have been described previously [15, 16]. The quality of substrates was always confirmed by detecting negative APAs in sera from cases without pituitary diseases.

At the time of onset, APAs were negative in the cytoplasmic region. However, in serum collected 3 months after vaccination, APAs were diffusely positive in the cytoplasmic region (Fig. 4). Double-staining with anti-ACTH, anti-TSH, anti-FSH, and anti-S-100beta antibodies, a marker for FSCs, showed overlap with APA-positive cells, but those with anti-LH, anti-PRL, and anti-GH antibodies showed no overlap (Fig. 5). We concluded that APAs were positive for corticotrophs, thyrotrophs, gonadotrophs, and FSCs.

Fig. 4

Immunostaining with the patient serum (left) and the control serum (right).

White arrowheads show the APA positive cells. Scale bar: 50 micro meters.

Fig. 5

Evaluation of anti-pituitary antibodies (APAs)

Indirect immunofluorescence (IIF) analysis using human anterior pituitary gland tissue. APA-positive cells were stained with serum collected 3 months after vaccination, which were merged with those stained with anti-adrenocorticotropic hormone (ACTH), anti-thyrotropin-releasing hormone (TSH), and anti-follicle-stimulating hormone (FSH) but not with anti-luteinizing hormone (LH), anti-prolactin (PRL), anti-growth hormone (GH) and anti S-100beta antibodies. White arrowheads show the cell where the patient’s serum is recognized. Scale bar: 50 micro meters.

Patient serum (10-fold dilution), anti-GH antibody (200-fold dilution, AF1067, R & D Systems), anti-PRL antibody (150-fold dilution, sc-7805, Santa Cruz Biotechnology), anti-ACTH antibody (50-fold dilution, abx430970, Abbexa), anti-TSH antibody (10-fold dilution, sc-7815, Santa Cruz Biotechnology), anti-FSH antibody (200-fold dilution, sc-7797, Santa Cruz Biotechnology), anti-LH antibody (50-fold dilution, Dr. Parlow’s Lab, National Hormone and Peptide Program, Harbor-UCLA Medical Center), anti-S100beta antibody (200-fold dilution, ab52642, Abcam) were used as primary antibodies. Donkey anti-Goat IgG Alexa Fluor 568 (500-fold dilution, A-11057, Molecular Probes), Donkey anti-human IgG Alexa Fluor 488 (400-fold dilution, 709-546-149, Jackson), Goat anti-rabbit IgG Alexa Fluor 568 (500-fold dilution, A-11036, Molecular Probes) were used as secondary antibodies.

This study was approved by the Ethical Committee of Nagoya University Hospital, (No. 2015-0273, 2018-0343-6), and the Ethical Committee of Shizuoka General Hospital (SGHIRB#2019086). Written informed consent was obtained from all patients prior to enrollment in the study.

Hypopituitarism associated with COVID-19 vaccines is a rare clinical condition, as indicated in a PubMed search in which eight documented cases were identified by the end of 2023. All these cases and our present case are summarized in Table 2. No consistency was found in the types of vaccines used in the patients who developed hypophysitis. The distribution by sex favors female (6 out of 9 cases). Among these cases, the manifestation of pituitary dysfunction varied, emerging within a time frame of 1 to 7 days post-vaccination, which is in alignment with the onset pattern observed in other clinical events. Hypopituitarism occurred following the initial or second COVID-19 vaccination in seven of the eight previous cases. Hypopituitarism ensued after the fourth vaccination in the remaining previously reported case and subsequent to receiving the fifth COVID-19 vaccine in our patient. Symptoms associated with hypophysitis after COVID-19 vaccination are similar to those of classical hypophysitis and include polyuria, headache, nausea, and vomiting. Five patients experiencing polyuria exhibited posterior pituitary insufficiency, with one of them additionally presenting concurrent anterior pituitary insufficiency; the remaining three cases exhibited only anterior pituitary insufficiency. Although most previous cases involved persistent pituitary insufficiency, pituitary function was partially recovered in our patient. Notably, the patient’s enlarged pituitary gland returned to its normal size as pituitary function was restored. Considering these findings, our case might be rare, but similar cases may have been overlooked among patients showing nonspecific symptoms after vaccination, such as headache and nausea.

Our patient had type 1 diabetes mellitus as an underlying condition. This is of interest given that, in the abovementioned reports, two of the eight patients also had immunological backgrounds (rheumatoid arthritis and Crohn disease) [8, 11]. The presence of latent autoimmunity could influence the development of vaccine-related pituitary dysfunction. Current reports on endocrinological rare clinical conditions associated with vaccination have emphasized the critical role of adjuvants within the vaccine in boosting adverse immune responses [17]. It is suggested that acquired immunity against pituitary glands may be induced, as evidenced by APA positivity, resulting in tissue damage to the pituitary gland.

APAs serve as a surrogate marker indicating the presence of autoimmunity against pituitary glands [13, 14] and are detected at a higher frequency in cases of some pituitary diseases, particularly biopsy-proven hypophysitis [15]. In the context of this case report, for the first time, we performed an evaluation of the presence of APAs in the serum of a patient experiencing pituitary insufficiency after COVID-19 vaccination. Samples taken 3 months after onset were positive for APAs against corticotrophs, gonadotrophs, and thyrotrophs. Given that corticotrophs and thyrotrophs were the target cells of the APAs in this case, it is presumed that these cells were damaged in the presence of anti-corticotroph and anti-thyrotroph antibodies, leading to reductions in ACTH and TSH secretion. However, the APAs may have developed secondary to hypophysitis. The causal relationship between APAs and hypophysitis remains to be fully elucidated.

In most cases of acquired IAD, the decrease in ACTH persists throughout life, and the plasma ACTH concentrations are extremely low. Among the previous reports of pituitary dysfunction after COVID-19 vaccination, there were some cases with very low plasma ACTH concentrations [4, 6]. Meanwhile, the decreased ACTH levels in our case were transient, and his plasma ACTH concentrations were relatively high. Although there is much speculation as to why this condition occurred, we considered three possibilities as follows. First, we found that APA-positive cells merged not only with ACTH-positive cells, but also with S-100beta-positive cells (Fig. 5). FSCs are known to be positive for S-100 protein and to have several functions, including intercellular communication, scavenger activity, and paracrine regulation of endocrine cells by producing various cytokines and chemokines [18]. FSCs were reported to suppress POMC expression and ACTH secretion through cytokines and chemokines such as interleukin (IL)-6 and C-X-C motif chemokine ligand (CXCL) 10 [19, 20]. Regarding acquired IAD, Fujita et al. demonstrated that some patients with acquired IAD had anti-FSC antibodies [21]. They also reported that acquired IAD was classified into an anti-corticotroph antibody-positive group and an anti-FSC antibody-positive group, with the former having extremely low plasma ACTH levels and the latter having relatively high plasma ACTH levels [21]. If the anti-FSC antibodies have a stimulating ability to promote IL-6 or CXCL10 secretion from FSCs, a mild functional impairment of corticotrophs may occur, resulting in acquired IAD with relatively high plasma ACTH levels, as noted in the present case. Second, BNT162b2 mRNA COVID-19 vaccination was reported to induce robust INF-gamma production [22, 23]. IFN-gamma can also induce expression of CXCL10 in certain types of FSCs [20]. Because our patient received an injection of BNT162b2 mRNA COVID-19 vaccine, an increased level of INF-gamma after vaccination may have promoted CXCL10 secretion from FSCs, resulting in a mild decrease in ACTH secretion. In this scenario, the presence of APAs would be secondary to pituitary damage. Third, a pharmacological dose of hydrocortisone was administered during the early stage of the disease, and this may have reduced the immune response, resulting in mild pituitary damage. Although various other possibilities should be considered, it is necessary to clarify this issue through the accumulation of case reports and basic research in the future.

Samples collected at a time point when plasma ACTH and serum cortisol concentrations were low (19 days after the fifth vaccination) were negative for APAs. The failure to detect anti-pituitary antibodies during this period may be partly owing to the low sensitivity of IF. However, although this phenomenon has only been documented in cases of autoimmune thyroiditis, some reports suggest that autoantibody titers might exhibit delayed elevation following inflammation owing to T-cell infiltration [24]. This implies a potential scenario in which the APAs titer remains low during the peak period and subsequently increases in cases involving the hypophysitis. Another potential contributing factor is that our patient was diagnosed with secondary adrenal insufficiency and received repeated high-dose glucocorticoids, which may have led to decreased serum APAs levels.

In conclusion, we presented a case of hypophysitis characterized by secondary adrenal insufficiency following COVID-19 vaccination with detection of APAs in the patient’s serum. The present case suggests a potential association between acquired immunity, APAs production, and pituitary damage. Despite rare occurrences, it is possible that patients who are similar to the patient in this case may be overlooked among those with nonspecific symptoms after vaccination against COVID-19. Monitoring and studying such cases will contribute to gaining more comprehensive knowledge regarding endocrine rare clinical conditions after COVID-19 vaccination.

We thank Mrs. Sakaguchi and other members of the Research Support Center at Shizuoka General Hospital for assistance with the ethics review. We thank Analisa Avila, MPH, ELS, of Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

No public or commercial funding was received.

S.I. is a member of the Editorial Board of Endocrine Journal. All other authors declare no conflicts of interest.

Signed informed consent was obtained directly from the patient.

The original data generated and analyzed during this study are included in the published article.

• 1   Menni  C,  Klaser  K,  May  A,  Polidori  L,  Capdevila  J, et al. (2021) Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis 21: 939–949.
• 2   Knudsen  B,  Prasad  V (2023) COVID-19 vaccine induced myocarditis in young males: a systematic review. Eur J Clin Invest 53: e13947.
• 3   Cancarevic  I,  Nassar  M,  Medina  L,  Sanchez  A,  Parikh  A, et al. (2022) Nephrotic syndrome in adult patients with COVID-19 infection or post COVID-19 vaccine: a systematic review. Cureus 14: e29613.
• 4   Morita  S,  Tsuji  T,  Kishimoto  S,  Uraki  S,  Takeshima  K, et al. (2022) Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report. BMC Endocr Disord 22: 185.
• 5   Taieb  A,  Mounira  EE (2022) Pilot findings on SARS-CoV-2 vaccine-induced pituitary diseases: a mini review from diagnosis to pathophysiology. Vaccines (Basel) 10: 2004.
• 6   Murvelashvili  N,  Tessnow  A (2021) A case of hypophysitis following immunization with the mRNA-1273 SARS-CoV-2 vaccine. J Investig Med High Impact Case Rep 9: 23247096211043386.
• 7   Roncati  L,  Manenti  A (2023) Pituitary apoplexy following adenoviral vector-based COVID-19 vaccination. Brain Hemorrhages 4: 27–29.
• 8   Bouça  B,  Roldão  M,  Bogalho  P,  Cerqueira  L,  Silva-Nunes  J (2022) Central diabetes insipidus following immunization with BNT162b2 mRNA COVID-19 vaccine: a case report. Front Endocrinol (Lausanne) 13: 889074.
• 9   Ankireddypalli  AR,  Chow  LS,  Radulescu  A,  Kawakami  Y,  Araki  T (2022) A case of hypophysitis associated with SARS-CoV-2 vaccination. AACE Clin Case Rep 8: 204–209.
• 10   Ach  T,  Kammoun  F,  Fekih  HE,  Slama  NBH,  Kahloun  S, et al. (2023) Central diabetes insipidus revealing a hypophysitis induced by SARS-CoV-2 vaccine. Therapie 78: 453–455.
• 11   Ishay  A,  Shacham  EC (2023) Central diabetes insipidus: a late sequela of BNT162b2 SARS-CoV-2 mRNA vaccine? BMC Endocr Disord 23: 47.
• 12   Matsuo  T,  Okubo  K,  Mifune  H,  Imao  T (2023) Bilateral optic neuritis and hypophysitis with diabetes insipidus 1 month after COVID-19 mRNA vaccine: case report and literature review. J Investig Med High Impact Case Rep 11: 23247096231186046.
• 13   Kobayashi  T,  Iwama  S,  Sugiyama  D,  Yasuda  Y,  Okuji  T, et al. (2021) Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors. J Immunother Cancer 9: 002493.
• 14   Iwama  S,  Arima  H (2020) Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands. Endocr J 67: 1077–1083.
• 15   Ricciuti  A,  De Remigis  A,  Landek-Salgado  MA,  De Vincentiis  L,  Guaraldi  F, et al. (2014) Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases. J Clin Endocrinol Metab 99: 1758–1766.
• 16   Iwama  S,  Welt  CK,  Romero  CJ,  Radovick  S,  Caturegli  P, et al. (2013) Isolated prolactin deficiency associated with serum autoantibodies against prolactin-secreting cells. J Clin Endocrinol Metab 98: 3920–3925.
• 17   Bragazzi  NL,  Hejly  A,  Watad  A,  Adawi  M,  Amital  H, et al. (2020) ASIA syndrome and endocrine autoimmune disorders. Best Pract Res Clin Endocrinol Metab 34: 101412.
• 18   Devnath  S,  Inoue  K (2008) An insight to pituitary folliculo-stellate cells. J Neuroendocrinol 20: 687–691.
• 19   Horiguchi  K,  Higuchi  M,  Yoshida  S,  Nakakura  T,  Tateno  K, et al. (2014) Proton receptor GPR68 expression in dendritic-cell-like S100β-positive cells of rat anterior pituitary gland: GPR68 induces interleukin-6 gene expression in extracellular acidification. Cell Tissue Res 358: 515–525.
• 20   Horiguchi  K,  Fujiwara  K,  Higuchi  M,  Yoshida  S,  Tsukada  T, et al. (2014) Expression of chemokine CXCL10 in dendritic-cell-like S100β-positive cells in rat anterior pituitary gland. Cell Tissue Res 357: 757–765.
• 21   Fujita  Y,  Bando  H,  Iguchi  G,  Iida  K,  Nishizawa  H, et al. (2021) Clinical heterogeneity of acquired idiopathic isolated adrenocorticotropic hormone deficiency. Front Endocrinol (Lausanne) 12: 578802.
• 22   Kurteva  E,  Vasilev  G,  Tumangelova-Yuzeir  K,  Ivanova  I,  Ivanova-Todorova  E, et al. (2022) Interferon-gamma release assays outcomes in healthy subjects following BNT162b2 mRNA COVID-19 vaccination. Rheumatol Int 42: 449–456.
• 23   Wang  X,  Yuen  TT,  Dou  Y,  Hu  J,  Li  R, et al. (2023) Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response. Nat Commun 14: 3440.
• 24   Kobayashi  T,  Iwama  S,  Yasuda  Y,  Okada  N,  Tsunekawa  T, et al. (2018) Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study. J Endocr Soc 2: 241–251.