Hypopituitarism with secondary adrenocortical insufficiency and arginine vasopressin deficiency due to hypophysitis after COVID-19 vaccination: a case report.

BACKGROUND: Although vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported. CASE PRESENTATION: An 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 µg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 µIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient's disease course was stable with continued thyroid and adrenal corticosteroid supplementation. CONCLUSIONS: Herein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Hypophysitis: Defining Histopathologic Variants and a Review of Emerging Clinical Causative Entities.

Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis is variable and diverse. Hypophysitis can be primary and idiopathic or autoimmune related, or secondary to local lesions, systemic disease, medications, and more. Although hypophysitis was previously accepted as an exceedingly rare diagnosis, a greater understanding of the disease process and new insights into possible etiologic sources have contributed to an increased frequency of recognition. This review provides an overview of hypophysitis, its causes, and detection strategies and management.

Preoperative differentiation of hypophysitis and pituitary adenomas using a novel clinicoradiologic scoring system.

PURPOSE: Hypophysitis can clinically and radiologically mimic other nonfunctioning masses of the sella turcica, complicating preoperative diagnosis. While sellar masses may be treated surgically, hypophysitis is often treated medically, so differentiating between them facilitates optimal management. The objective of our study was to develop a scoring system for the preoperative diagnosis of hypophysitis. METHODS: A thorough literature review identified published hypophysitis cases, which were compared to a retrospective group of non-functioning pituitary adenomas (NFA) from our institution. A preoperative hypophysitis scoring system was developed and internally validated. RESULTS: Fifty-six pathologically confirmed hypophysitis cases were identified in the literature. After excluding individual cases with missing values, 18 hypophysitis cases were compared to an age- and sex-matched control group of 56 NFAs. Diabetes insipidus (DI) (p < 0.001), infundibular thickening (p < 0.001), absence of cavernous sinus invasion (CSI) (p < 0.001), relation to pregnancy (p = 0.002), and absence of visual symptoms (p = 0.007) were significantly associated with hypophysitis. Stepwise logistic regression identified DI and infundibular thickening as positive predictors of hypophysitis. CSI and visual symptoms were negative predictors. A 6-point hypophysitis-risk scoring system was derived: + 2 for DI, + 2 for absence of CSI, + 1 for infundibular thickening, + 1 for absence of visual symptoms. Scores ≥ 3 supported a diagnosis of hypophysitis (AUC 0.96, sensitivity 100%, specificity 75%). The scoring system identified 100% of hypophysitis cases at our institution with an estimated 24.7% false-positive rate. CONCLUSIONS: The proposed scoring system may aid preoperative diagnosis of hypophysitis, preventing unnecessary surgery in these patients.

Hypophysitis.

OBJECTIVE: Hypophysitis is considered a rare inflammatory disease of the pituitary gland. For a long time, primary autoimmune hypophysitis has stood out as the most relevant type of hypophysitis. However, with the advent of immunotherapy for the treatment of malignancies and identification of hypophysitis as an immune-related adverse event, hypophysitis has garnered increasing interest and recognition. Therefore, awareness, early recognition, and appropriate management are becoming important as the indication for immunomodulatory therapies broaden. METHODS: In this review, we discuss the epidemiology, diagnosis, and treatment of hypophysitis with a focus on recent data and highlight subtypes of particular interest while recognizing the gaps in knowledge that remain. RESULTS: Regardless of cause, symptoms and signs of hypophysitis may be related to mass effect (headache and visual disturbance) and hormonal disruption that warrant prompt evaluation. In the vast majority of cases, a diagnosis of hypophysitis can be made presumptively in the appropriate clinical context with radiologic findings consistent with hypophysitis and after the exclusion of other causes. CONCLUSION: Although subtle differences currently exist in management and outcome expectations between primary and secondary causes of hypophysitis, universally, treatment is aimed at symptom management and hormonal replacement therapy.

The imaging of immunotherapy-related hypophysitis and other pituitary lesions in oncology patients.

Immunotherapy has revolutionised the treatment of metastatic disease from a variety of different primaries, but is frequently associated with immune-related adverse events. This review illustrates the imaging features of immunotherapy-related hypophysitis (IH) and some of the important differential diagnoses in oncology patients. The key radiological characteristic of IH is diffuse, modest enlargement of the pituitary gland with temporal evolution attributable to immunotherapy. Pituitary enlargement is transient, and the gland size returns to baseline size or smaller within months. IH is usually associated with homogeneous enhancement of the pituitary gland, and the pituitary stalk may be thickened. Larger pituitary size, deviation of the pituitary stalk, the presence of a discrete lesion surrounding by normal pituitary tissue, sellar expansion, and clival invasion are not typical of IH and suggest alternate diagnoses. On integrated 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (PET)/computed tomography (CT), a transient increase in the metabolic activity of the pituitary gland with subsequent decline to background activity is also suggestive of IH. We suggest that the sella is assessed routinely on imaging performed in the first 6 months after commencing immunotherapy to detect subtle changes. Radiologists should also be aware of features that either support a diagnosis of IH or suggest alternate diagnoses.

Two cases of symptomatic secondary hypophysitis due to Rathke's cleft cysts treated with glucocorticoids: long-term follow-up.

Rathke's cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.

Emergency Presentations of Immune Checkpoint Inhibitor-Related Endocrinopathies.

BACKGROUND: Immune checkpoint inhibitors (ICI) are an important component of anticancer treatment, with indications across an increasing range of oncological diagnoses. ICIs are associated with a range of immune-mediated toxicities. Immune-related endocrinopathies pose a distinct challenge, given the nonspecific symptom profile and potentially life-threatening sequelae if not recognized. OBJECTIVES: To determine the frequency and clinical presentations of immune-mediated endocrinopathies in patients treated with ICIs presenting as emergencies. METHODS: A prospective observational cohort study was undertaken at a specialist oncology hospital in North West England from May 20, 2018 to May 19, 2020. Within the hospital, the Oncology Assessment Unit (OAU) acts as the receiving unit in which assessments are undertaken of all emergency presentations. All patients treated with ICIs presenting to the OAU were included. The primary outcome was diagnosis of an immune-mediated endocrinopathy. Length of inpatient stay, and 7- and 30-day mortality rates were examined. RESULTS: During the study period, 684 patients treated with ICIs presented to the OAU. Twenty-four (3.5%) patients had an acute immune-mediated endocrinopathy, of which 17 had hypophysitis, 4 diabetes mellitus, 2 thyrotoxicosis, and 1 adrenalitis. Median length of stay for patients with hypophysitis was 1 day. No patient with an immune-mediated endocrinopathy died within 30 days of presentation. CONCLUSIONS: Presentations to emergency settings with acute immune-mediated endocrinopathies are rare. Early recognition of immune-mediated toxicities is important, and particularly pertinent in ICI-related endocrinopathies, where even in life-threatening cases, the presentation can be vague and nonspecific.

Hypophysitis (Including IgG4 and Immunotherapy).

Hypophysitis is characterized by inflammation of the pituitary gland that can be primary (PH) or secondary (SH) to other diseases or following drug administration. It may also be classified according to anatomical and histopathological criteria, leading to variable degrees of hypopituitarism and/or compressive symptoms to nearby structures. There has recently been an increase in the number of hypophysitis cases, raising the interest on the spectrum of its pathogenesis, clinical, biochemical/endocrinological, and imaging features. However, the use of conventional biomarkers, including currently utilized pituitary autoantibodies, has relatively limited diagnostic accuracy. Lymphocytic hypophysitis (LH) is the commonest cause of PH, whereas IgG4-related hypophysitis is increasingly being recognized. Histiocytosis and granulomatous diseases are the most frequent causes of SH, although infections and lymphoma have also been reported. The increasing use of immune checkpoint inhibitors in oncology is associated with a high incidence of hypophysitis, providing further understanding of its pathogenesis. Hypophysitis can occur silently and be easily missed, potentially leading to substantial morbidity or mortality due to adrenal insufficiency, requiring a high index of clinical suspicion and timely initiation of appropriate treatment. In most cases of LH or drug-induced hypophysitis, active surveillance along with replacement of established hormonal deficiencies is needed. In the presence of compressive and/or evolving symptoms, treatment with glucocorticoids either alone or in combination with other immunosuppressive agents can be used. Surgical decompression is reserved for nonresponsive cases with threatened vital structures. Timely diagnosis and intervention are important to minimize disease-related morbidity and mortality. We aimed to review current concepts and recent developments in the pathogenesis, diagnosis, and management of hypophysitis.

Clinical Characteristics, Management, and Treatment Outcomes of Primary Hypophysitis: A Monocentric Cohort.

Primary hypophysitis (PH) is a rare autoimmune inflammatory disease of the pituitary gland. The aim of the study was to evaluate clinical characteristics, disease management, and outcomes of cases with PH. Medical records of PH patients admitted to Hacettepe University Hospital between 1999 and 2017 were analyzed retrospectively. Paraffin-embedded pathology blocks were obtained for both re-examination and IgG4 immunostaining. Twenty PH patients (15 females, 5 males) were evaluated. Mean age at diagnosis was 41.5±13.4 years. Some form of hormonal disorder was present in 63.2% of cases, hypogonadism (66.6%) being the most common. Panhypopituitarism was present in 36.8%. All patients had pituitary gland enlargement on magnetic resonance imaging; stalk thickening and loss of neurohypophyseal bright spot were present in 17.6 and 23.5%, respectively. Lymphocytic hypophysitis was the most common histopathological subtype (50%). Among pathology specimens available for IgG and IgG4 immunostaining (n=10), none fulfilled the criteria for IgG4-related hypophysitis. Four patients were given glucocorticoid treatment in diverse protocols; as initial therapy in 3. Sixteen cases underwent surgery, 7 of whom due to neuro-ophthalmologic involvement. Only 1 patient was observed without any intervention. Reduction of pituitary enlargement was seen in all surgical and glucocorticoid treated cases. None of the surgical patients showed hormonal improvement while one case in glucocorticoid group improved. PH should be considered in the differential diagnosis of sellar masses causing hormonal deficiencies. MRI findings are usually helpful, but not yet sufficient for definitive diagnosis of PH. Treatment usually improves symptoms and reduces sellar masses while hormonal recovery is less common.

When polyuria does not stop: a case report on an unusual complication of hantavirus infection.

BACKGROUND: The clinical features, course and outcome of hantavirus infection is highly variable. Symptoms of the central nervous system may occur, but often present atypically and diagnostically challenging. Even though the incidence of hantavirus infection is increasing worldwide, this case is the first to describe diabetes insipidus centralis as a complication of hantavirus infection in the Western world. CASE PRESENTATION: A 49-year old male presenting with severe headache, nausea and photophobia to our neurology department was diagnosed with acute haemorrhage in the pituitary gland by magnetic resonance imaging. In the following days, the patient developed severe oliguric acute kidney failure. Diagnostic workup revealed a hantavirus infection, so that the pituitary haemorrhage resulting in hypopituitarism was seen as a consequence of hantavirus-induced hypophysitis. Under hormone replacement and symptomatic therapy, the patient's condition and kidney function improved considerably, but significant polyuria persisted, which was initially attributed to recovery from kidney injury. However, water deprivation test revealed central diabetes insipidus, indicating involvement of the posterior pituitary gland. The amount of urine production normalized with desmopressin substitution. CONCLUSION: Our case report highlights that neurological complications of hantavirus infection should be considered in patients with atypical clinical presentation.

The Impact of Photoperiod on the Leptin Sensitivity and Course of Inflammation in the Anterior Pituitary.

Leptin has a modulatory impact on the course of inflammation, affecting the expression of proinflammatory cytokines and their receptors. Pathophysiological leptin resistance identified in humans occurs typically in sheep during the long-day photoperiod. This study aimed to determine the effect of the photoperiod with relation to the leptin-modulating action on the expression of the proinflammatory cytokines and their receptors in the anterior pituitary under physiological or acute inflammation. Two in vivo experiments were conducted on 24 blackface sheep per experiment in different photoperiods. The real-time PCR analysis for the expression of the genes IL1B, IL1R1, IL1R2, IL6, IL6R, IL6ST, TNF, TNFR1, and TNFR2 was performed. Expression of all examined genes, except IL1ß and IL1R2, was higher during short days. The leptin injection increased the expression of all examined genes during short days. In short days the synergistic effect of lipopolysaccharide and leptin increased the expression of IL1B, IL1R1, IL1R2, IL6, TNF, and TNFR2, and decreased expression of IL6ST. This mechanism was inhibited during long days for the expression of IL1R1, IL6, IL6ST, and TNFR1. The obtained results suggest the occurrence of leptin resistance during long days and suggest that leptin modulates the course of inflammation in a photoperiod-dependent manner in the anterior pituitary.

Cancer immunotherapy-associated hypophysitis.

The advances in cancer therapy have included the development of drugs that inhibit immune checkpoint ligands. Two types of immune checkpoint inhibitors, both antibodies that target CTLA-4 and PD-1, have been approved for its use in NSCLC and melanoma as first-line or second-line therapy. Sadly, not desirable consequences of immunotherapy are immune-related adverse events. immune-related hypophysitis is the most common endocrine adverse event after thyroid disfunction. The particularity of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if this form of therapy is used in the future for earlier stages of cancer. Therefore, hypophysitis represents a challenge for the physician, sometimes occurring without specific symptomatology and which should be considered for clinical management. In this review, we describe the current data regarding the pathophysiology and management for immune-related hypophysitis.

[A Surgical Case of Aseptic Meningitis and Secondary Hypophysitis due to Rupture of a Rathke's Cleft Cyst].

PURPOSE: We describe a surgical case of aseptic meningitis and secondary hypophysitis due to rupture of a Rathke's cleft cyst(RCC)and report on literature considerations. CASE: A 36-year-old woman with a past history of menstrual irregularity who had been taking a low-dose contraceptive for five years visited our hospital. She had discomfort in her right eye four years earlier. A waxy nodule observed on MRI was diagnosed to be an asymptomatic RCC. She experienced periodic headaches and retrobulbar pain without any prior history. MRI showed dural thickening on gadolinium-T1-weighted(GdT1)imaging, disappearance of the waxy nodule on T1/T2-weighted imaging, signal change of the cyst contents, and suspected cerebrospinal fluid in the pre-pontine cistern. Aseptic meningitis or hemorrhagic adenoma due to RCC rupture was suspected, and endoscopic transsphenoidal surgery was performed on day 26. The pathological results indicated that the ruptured RCC had resulted in aseptic meningitis and secondary hypophysitis. CONCLUSION: If the rupture of an RCC is suspected and subsequent secondary hypophysitis and optic neuritis are observed, early diagnosis and surgery with informed consent are essential. This is because of the high risk for panhypopituitarism with vision loss and visual field disturbance.

New Molecular, Biological, and Immunological Agents Inducing Hypophysitis.

Hypophysitis is a relatively rare disease that exerts a strong autoimmune component encompassing different etiologies. Immunomodulatory drugs, such as interferon-α, are known to rarely induce hypophysitis. In recent years, a large number of new biological and immunomodulatory agents have been introduced into clinical practice. Although immune-suppressing agents used for the treatment of autoimmune disorders only rarely are associated with hypophysitis, it is commonly encountered with immunomodulatory agents used for the treatment of cancer. Hypophysitis related to anti-cytotoxic T-lymphocyte-associated antigen-4 antibodies (anti-CTLA-4 Abs) occurs with a prevalence ranging from 0 to 18% and is considered a distinctive side effect of anti-CTLA-4 Abs treatment. Hypophysitis due to the programmed cell death protein-1 antibodies and their ligand is less common, its frequency ranging from 0 to 0.8%. No cases of hypophysitis have been described with molecular targeted agents. Diagnosis of hypophysitis still remains clinical since anti-pituitary antibodies are not a sensitive marker and thus its true prevalence is probably underestimated. The pathophysiology of hypophysitis induced by anticancer agents is not fully clarified. In most cases, treatment requires dose adjustment of the offending drug and pituitary hormone replacement. This mini-review aims to present currently available information regarding hypophysitis related to new molecular, biological, and immunological agents.

Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series.

Hypophysitis that develops in cancer patients treated with monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; an inhibitory molecule classically expressed on T cells) is now reported at an incidence of approximately 10%. Its pathogenesis is unknown, in part because no pathologic examination of the pituitary gland has been reported to date. We analyzed at autopsy the pituitary glands of six cancer patients treated with CTLA-4 blockade, one with clinical and pathologic evidence of hypophysitis, one with mild lymphocytic infiltration in the pituitary gland but no clinical signs of hypophysitis, and four with normal pituitary structure and function. CTLA-4 antigen was expressed by pituitary endocrine cells in all patients but at different levels. The highest levels were found in the patient who had clinical and pathologic evidence of severe hypophysitis. This high pituitary CTLA-4 expression was associated with T-cell infiltration and IgG-dependent complement fixation and phagocytosis, immune reactions that induced an extensive destruction of the adenohypophyseal architecture. Pituitary CTLA-4 expression was confirmed in a validation group of 37 surgical pituitary adenomas and 11 normal pituitary glands. The study suggests that administration of CTLA-4 blocking antibodies to patients who express high levels of CTLA-4 antigen in the pituitary can cause an aggressive (necrotizing) form of hypophysitis through type IV (T-cell dependent) and type II (IgG dependent) immune mechanisms.

Paraneoplastic isolated adrenocorticotropic hormone deficiency revealed after immune checkpoint inhibitors therapy: new insights into anti-corticotroph antibody.

Introduction: A recently discovered facet of paraneoplastic adrenocorticotropic hormone (ACTH) deficiency exists in two forms: a paraneoplastic spontaneous isolated ACTH deficiency (IAD) and an immune checkpoint inhibitor (ICI)-related hypophysitis. Autoantibodies against corticotrophs, such as circulating anti-proopiomelanocortin (POMC) antibodies are considered disease markers. However, the number of identified cases was limited, implying that the characteristics of these autoantibodies are not fully understood. Methods: We investigate circulating autoimmune autoantibodies in detail through a novel case of IAD that developed as a paraneoplastic autoimmune ACTH deficiency. Results: The patient developed IAD after 25 weeks of ICI therapy for metastasis of large-cell neuroendocrine carcinoma at 69 years of age. Ectopic ACTH expression and infiltration of CD3+, CD4+, CD8+, and CD20+ lymphocytes were observed in the tumor tissues and circulating anti-POMC antibodies were detected specifically in the patient's serum. Moreover, detailed analyses of immunofluorescence staining using patient serum revealed that the recognition site of the autoantibody was ACTH25-39, which had not been identified in previous cases of paraneoplastic autoimmune ACTH deficiency. Conclusion: This case involved a combination of paraneoplastic spontaneously acquired IAD and ICI-related hypophysitis occupying the middle ground. Moreover, our study reveals new aspects of anti-POMC antibodies in patients with paraneoplastic ACTH deficiency. This report expands our understanding of the immunological landscape and provides new insights for the identification of antibodies associated with paraneoplastic autoimmune ACTH deficiency.

Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy.

Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.

Paraneoplastic autoimmune hypophysitis: An emerging concept.

Pituitary autoimmunity is one of the principal causes of hypopituitarism. Additionally, hypophysitis is one of the immune-related adverse events associated with immunotherapy. Recent case-oriented research has revealed a novel type of autoimmune hypophysitis, anti-PIT-1 hypophysitis, related to isolated adrenocorticotropic hormone (ACTH) deficiency and immune checkpoint inhibitor-related hypophysitis, as a form of paraneoplastic syndrome. Under these conditions, the ectopic expression of pituitary antigens present in tumors evokes a breakdown of immune tolerance, resulting in the production of autoantibodies and autoreactive cytotoxic T cells that specifically harm pituitary cells. Consequently, an innovative clinical entity of paraneoplastic autoimmune hypophysitis has been purported. This novel concept and its underlying mechanisms provide clues for understanding the pathogenesis of autoimmune pituitary diseases and can be applied to other autoimmune diseases. This review discusses the etiology of paraneoplastic autoimmune hypophysitis and its future.

The novel concept of "Onco-Immuno-Endocrinology" led to the discovery of new clinical entity "paraneoplastic autoimmune hypophysitis".

Recent advances in tumor immunology have enabled to develop immune checkpoint inhibitors and to save many patients with advanced cancer. Various endocrine diseases are caused by autoimmune mechanisms; it is important to understand that many endocrine organs are targeted by autoimmunity. In addition, some of malignant tumors ectopically produce hormones and lead to a clinically relevant ectopic hormone syndrome as an endocrine paraneoplastic syndrome. Thus, interplay between oncology, immunology, and endocrinology is important. We have defined a new clinical entity "paraneoplastic autoimmune hypophysitis" as "hypophysitis associated with autoimmunity against pituitary antigens caused by an ectopic expression of these antigens in the tumor and resulting in a breakdown of immune tolerance". To understand the pathophysiology of paraneoplastic autoimmune hypophysitis requires a fusion of the fields of oncology, immunology, and endocrinology; therefore, I propose a new concept of Onco-Immuno-Endocrinology.