Pituitary disorders following COVID-19 vaccination have been documented in 23 case reports, which are summarized in Table 2. These primarily encompass cases of pituitary apoplexy (PA) and hypophysitis, alongside other dysfunctions such as Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and isolated adrenocorticotroph hormone (ACTH) deficiency (IAD). In the subsequent paragraphs, we provide an accurate review covering epidemiology, clinical presentation, imaging findings, treatments, outcomes, and potential pathogenesis of the primary pituitary diseases occurring post COVID-19 vaccination.

Post COVID-19 vaccination hypophysitis was reported in 9 patients, with a female-to-male ratio of 2:1. The average age of the affected individuals was 46.5 years (ranging from 16 to 74), including one previously healthy adolescent [8]. The majority of patients (88%) received a mRNA vaccine, with Pfizer/BioNTech (63%) and Moderna being the most common. Only one patient received the viral vector AstraZeneca vaccine. Notably, hypophysitis occurred regardless of the vaccine dose number, and only one clinical report noted testing negative for SARS-CoV-2 via nasopharyngeal swab [8]. Concerning patients’ clinical history, three female patients presented with obesity [9,10,11], three with autoimmunity, being affected respectively with Crohn’s disease, rheumatoid arthritis and Hashimoto’s thyroiditis and one female patient had stable myelodysplastic syndrome [11,12,13,14]. Additionally, one patient had a previously identified space-occupying sellar lesion [15].

All patients experienced symptoms, with a minority developing mild symptoms shortly after the first vaccination, which worsened following the second dose [8, 9, 16]. Most of the patients (78%) sought medical attention due to symptoms acute onset associated with vasopressin (AVP) deficit, presenting with polyuria, intense thirst and polydipsia [8,9,10,11,12,13,14]. A smaller proportion of patients reported associated weight loss [8, 12] and headache [9]. Laboratory evaluation typically revealed elevated serum and low urine osmolality [9, 10, 12, 14], with 43% of them exhibiting hypernatremia [10, 12, 14]. Notably, one patient, in addition to ADH deficiency, experienced transient amenorrhea with low gonadotropins and IGF-1 levels, which recovered 5 months post-vaccination [9]. In two male patients, hypophysitis manifested with anterior pituitary involvement [15, 16]. One patient displayed symptoms including nausea, vomiting, mid-epigastric pain, fatigue, and hyponatremia, with laboratory findings confirming severe, secondary adrenal insufficiency, central hypothyroidism, and hypogonadism [16]. Similarly, the other patient presented with symptoms and laboratory results consistent with adrenal insufficiency, central hypothyroidism and growth hormone deficiency [15]. Lastly, a case report presented by Matsuo et al. documented hypophysitis associated with optic neuritis [14].

Magnetic resonance imaging (MRI) displayed pituitary stalk thickening in 70% of the patients [8,9,10,11,12, 14, 16], while the absence of high intensity (bright) signal in the posterior pituitary on T1 weighted imaging was described in 5 patients, all showing ADH deficiency [8, 11,12,13,14]. Pituitary gland enlargement was described in only 2 patients [14, 16].

Desmopressin (DDAVP) was promptly administered in all patients with ADH deficiency [8,9,10, 13, 14], while glucocorticoid and thyroid hormone replacement therapy was established in patients with anterior pituitary dysfunction [15, 16]. Steroid treatment with methylprednisolone was employed only in a patient exhibiting bilateral optic neuritis [14].

Most of the patients with ADH deficiency still required treatment at the time of the last reported evaluation, with the longest documented follow-up period being 18 months [12]. Nevertheless, one case reported complete withdrawal of DDAVP therapy and spontaneous full recovery from ADH deficiency [11]. Regarding patients with anterior pituitary dysfunction, progression to complete hypopituitarism was described in a patient with a sellar cystic lesion who declined surgical intervention [15].

No biopsy data are available; diagnosis relied primarily on clinical and radiological findings. Additionally, autoantibodies were not tested, as noted by some Authors [8, 11]. COVID-19 vaccination was implicated as the causative agent due to its close temporal association with symptoms and the exclusion of common causes of hypophysitis. Three patients had autoimmune predisposition, suggesting a potential autoimmune basis. Authors speculated that hypophysitis may have been triggered by pro-inflammatory state, immunological derangements induced by COVID-19 vaccination, as well as by adjuvants and cross-reactivity mechanisms related to the SARS-CoV-2 spike protein [8,9,10,11, 13, 14]. Some Authors hypothesized that vaccine-related hypophysitis could be similar to autoimmune hypophysitis due to immune checkpoint inhibitors (ICI) therapy, except for time of onset (shorter for vaccines) [12, 16].

Post COVID-19 vaccination PA was documented in 6 cases, with an equal sex distribution [17,18,19,20,21,22]. Mean age was 38 years (range 24–50), being significantly lower in females compared to males (30 vs. 46, p = 0.01). Data regarding the vaccine type are available for 5 out of 6 patients. Among these, 3 received a viral vector vaccine (AstraZeneca) while 2 received an mRNA vaccine (Pfizer/BioNTech and Moderna). PA occurred following the 2nd vaccine dose in 3 patients [19, 20, 22] and after the 3rd dose in 1 patient [17]. In one case, initial symptom appeared after the 1st vaccine inoculation (fever for 24 h, headache for 1 month) and intensified after the 2nd dose, accompanied by hyperprolactinemia and amenorrhea prompting MRI evaluation [21]. Nasopharyngeal swabs were used to detect SARS-CoV-2 infection in 3 patients, all yielding negative results [17, 19, 20]. The presence of a pituitary neuroendocrine tumor (PitNET) was generally unknown, except for one patient who had already been diagnosed with a giant PitNET and partial hypopituitarism [19]. Other potential predisposing factors were not highlighted by the Authors.

PA symptoms occurred shortly after vaccine inoculation, regardless of the vaccine type, with a mean onset delay of 3 days (range 1–5). All patients experienced high-intensity headache, predominantly frontal, characterized by sudden onset and resistance to over-the-counter analgesics. Additionally, headache was variably associated with nausea or vomit, that was present in 2 out of 6 patients [17, 19]; 3 out of 6 patients displayed visual disturbances [17, 19, 22], 2 out of 6 had fever [17, 22] and one out of 6 presented with altered mental status [22]. Two patients presented with hypotension at hospital admission [17, 22]. Regarding hormonal dysfunction, Aliberti et al. documented secondary hypogonadism; ACTH and cortisol were not investigated as the patient promptly underwent dexamethasone treatment due to suspected adrenal insufficiency [17]. No confirmed hypersecretions were reported by other Authors, except for hyperprolactinemia associated with amenorrhea in the study by Roncati et al., which was attributed to the pituitary stalk disconnection effect [21]. ADH deficiency was never reported.

MRI revealed the presence of a giant pitNET in 2 patients [19, 22], macropitNET in 1 patient [17], and a possible micropitNET in 1 patient [18]. Male patients presented with larger pituitary tumors, consistent with the typical diagnostic delay in this gender group [23]. MRI findings showed features of PA, such as signal alterations indicative of recent hemorrhage, mass effect and compression of surrounding structures. Optic chiasm involvement was documented in 4 patients [17,