Abstract
Summary
Primary hypophysitis is a rare disease that may have variable clinical presentations. The main treatment options are clinical observation, immunosuppressive drugs, and surgery. Glucocorticoids are used as first-line medical therapy; however, non-responsiveness and recurrences are the major problems. We present a 30-year-old male patient who had an excellent radiologic response to a single course of glucocorticoids. The patient presented with malaise and severe headaches of acute onset. Cranial MRI revealed a pituitary mass compressing the optic chiasm. Hormonal evaluation studies were consistent with anterior pituitary hormone dysfunction except for the growth hormone axis. There was a mild compression on the optic chiasm in the pituitary MRI. The patient was started on methylprednisolone therapy at a dose of 80 mg/day. The pituitary MRI revealed complete regression of the mass after 2 months, and there was a complete recovery of pituitary functions after 6 months. There is no consensus on the optimal dose and duration of glucocorticoid therapy for primary hypophysitis in the literature. We report that steroid therapy, even in lower doses, might be effective in mild-to-moderate cases.
Learning points
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Primary hypophysitis is a rare disease with a varied clinical course, and hence the treatment strategies should be individualized.
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There is no consensus on the optimal dose and duration of glucocorticoid therapy.
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Glucocorticoid therapy may induce complete remission in some patients, especially with a mild-to-moderate disease course and during the acute phase of the disease.
Background
The term ‘hypophysitis’ defines the inflammatory processes of the pituitary gland which might either occur in isolation as ‘primary hypophysitis’ or be caused by an underlying systemic disease and known as ‘secondary hypophysitis’. Hypophysitis is a rare disease with a reported prevalence of 1/9 million, which is most probably an underestimate considering secondary etiologies (1).
Primary hypophysitis is classified according to histologic characteristics. Lymphocytic hypophysitis is the most common subtype followed by granulomatous hypophysitis. Xanthomatous, necrotizing, mixed, and IgG4-related types are the other subtypes. Definitive differential diagnosis of hypophysitis and its subtypes is only possible with pathologic investigation. However, the diagnosis is frequently based on clinical and radiologic findings to avoid the risks of invasive procedures. Inflammation of the pituitary gland may cause impairments in hormone secretion as well as mass effects compressing neighboring structures. The most common symptoms are headache, malaise, vision problems, hypogonadal symptoms, and polyuria/polydipsia (1).
The main treatment options for primary hypophysitis are clinical observation, glucocorticoids and other immunosuppressive drugs, surgery, and radiotherapy (1, 2). Primary hypophysitis is a rare disease, and the treatment algorithms are not optimally defined, thus the therapeutic strategies are mainly decided upon the clinical course and radiologic findings (1). Mild cases might be observed without interventions, while surgery may be preferred in patients with severe disease who need decompression and in those with an equivocal diagnosis (3). Glucocorticoids are the first-line medical therapy, and other immunosuppressives such as azathioprine, cyclosporine, and rituximab may be used in cases of non-responsiveness or recurrence (3). Despite growing literature, the optimal dose and duration of glucocorticoids are not known yet. Here, we present a patient with primary hypophysitis who had an excellent response following a single dose of glucocorticoids.
Case presentation
A 30-year-old male patient presented to the Department of Neurology with a 2-month history of severe headache unrelieved by analgesics. He did not have accompanying nausea or vomiting, but he complained of malaise. He was otherwise healthy with no history of chronic disease or any use of medications.
Investigation
The cranial MRI ordered by the neurologist revealed a pituitary mass, and the patient was directed to the Department of Endocrinology. His vital signs were normal. A systemic physical examination and complete neurologic examination showed no pathologic signs. Results of a visual field examination were within normal limits. The patient was obese with a body mass index of 30 kg/m2 (weight: 114 kg).
The complete blood count was normal with no leukocytosis or neutrophilia, but the acute-phase reactants were slightly elevated with a C-reactive protein of 7.3 ng/dL (<5 ng/dL) and an erythrocyte sedimentation rate of 26 mm/h (<15 mm/h). The blood glucose, lipid profile, and renal and liver function test results were normal. The patient had mild hypercalcemia (Ca: 11.3 mg/dL, reference: 8.6–10.2) with no hyperparathyroidism. Pituitary hormone analysis revealed central adrenal insufficiency, central hypothyroidism, and central hypogonadism with increased serum prolactin levels (Table 1). The serum insulin-like growth factor-1 (IGF-1) level was above the reference limits for age and sex, but the growth hormone level was suppressed following a 75-g oral glucose tolerance test (Table 1). The high IGF-1 was assumed to be associated with insulin resistance. The patient had no polydipsia/polyuria, and serum and urine osmolalities were normal.
Laboratory analyses during presentation and 6 months following glucocorticoid therapy.
Laboratory analysis | At presentation | Sixth month | Reference range |
---|---|---|---|
Cortisol (8:00 h, fasting) (µg/dL) | 1.68 | 12.05 | 4.82–19.5 |
Peak cortisol (µg/dL)† | 9.06 | 16.41 | – |
ACTH (pg/mL) | 12.92 | 18.35 | 7.2–63.3 |
Free T4 (ng/dL) | 0.813 | 1.28 | 0.93–1.7 |
TSH (µıu/mL) | 0.192 | 2.65 | 0.27–4.2 |
Total testosterone (ng/mL) | <0.25 | 4.72 | 2.8–8 |
LH (mIU/mL) | 0.576 | 5.07 | 1.7–8.6 |
FSH (mIU/mL) | 4.89 | 13.93 | 1.5–12.4 |
IGF-1 (µg/L) | 264.0 | 169 | 71.2–234* |
GH (ng/mL) | 1.81 | 0.064 | 0.05–3 |
Prolactin (ng/mL) | 49.03 | 19.72 | 4.6–21.4* |
DHEA-S (µ/dL) | 57.06 | 140 | 160–449 |
Serum osmolality (mOsm/kg) | 293 | NA | – |
Urine osmolality (mOsm/kg) | 528 | NA | – |
Anti-Tg (IU/mL) | 224.3 | NA | <115 |
Anti-TPO (IU/mL) | 567.2 | <34 | |
Alpha-fetoprotein (ng/mL) | 3.89 | NA | <7 |
β-hCG (mIU/mL) | <0.1 | <2.6 | |
β-2 microglobulin (mg/L) | 1.53 | NA | 0.7–1.8 |
IgG4 (mg/dL) | 80 | NA | 8–140 |
Anti-dsDNA, anti-SSA/Ro, anti-Smith, anti-RNP, | Negative | NA | – |
ANCA, RF, ACE (U/L) | 45 | NA | 8–52 |
Adenosine deaminase (U/L) | 8.9 | NA | <15 |
QuantiFERON-TB test (IU/mL) | 10 | 10 | <0.35 |
*The reference range is adjusted for age and gender; †determined by 250 mcg ACTH stimulation test.
ACE, angiotensin-converting enzyme; ACTH, adrenocorticotropic hormone; ANCA, antineutrophil cytoplasmic antibody; anti-dsDNA, anti-double-stranded DNA; anti-RNP, antinuclear ribonucleoprotein; anti-SSA/Ro, anti-Sjögren's syndrome-related antigen A; β-hCH, beta human chorionic gonadotropin; DHEA-S, dehydroepiandrosterone-sulfate; FSH, follicle-stimulating hormone; GH, growth hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; NA, not available; OGTT, oral glucose tolerance test; RF, rheumatoid factor; TSH, thyroid-stimulating hormone.
MRI of the pituitary was done to further characterize the mass. The intrasellar lesion was 18 mm in the midline on coronal sections, extending to the suprasellar cistern and compressing the optic chiasm (Fig. 1). There was a triangular pituitary enlargement with a thickened stalk and increased contrast enhancement. These findings pointed primarily to the diagnosis of hypophysitis, as reported previously (4).
Baseline pituitary MRI. The coronal (upper row) and sagittal (lower row) T2-weighted (A and D) and T1-weighted (unenhanced (B and E) and enhanced (C and F)) images show a triangular pituitary enlargement with marked heterogeneous signal intensity and contrast enhancement. The stalk is prominently thick with increased contrast enhancement. Dural thickening with contrast enhancement is observed along the clivus, and the signal intensity of the superior part of the clivus is heterogeneous. The bright spot of the neurohypophysis is in the normal position, and mucosal thickening is detected in the sphenoid sinus. The lesion in the left middle cranial fossa is consistent with an arachnoid cyst.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-23-0125
After the diagnosis of hypophysitis, further tests were done to exclude any diseases that may have caused secondary hypophysitis (Table 1). The results revealed accompanying Hashimoto’s thyroiditis with high serum autoantibody titers and heterogeneous echogenicity of the thyroid gland on ultrasound. The normal levels of serum tests (e.g. angiotensin-converting enzyme and β-2 microglobulin) cannot exclude the presence of underlying systemic disease, and, as the QuantiFERON-TBtest result was significantly high, further imaging studies were done. The postero-anterior chest x-ray and chest computed tomography (CT) revealed no infiltrations or hilar lymphadenopathies. The whole-body imaging by 18F-FDG positron emission tomography-CT (PET-CT) was suggested in previous guidances as an effective imaging modality to detect lesions secondary to systemic diseases (1). 18F-FDG PET-CT was performed in the case to exclude probable systemic diseases along with tuberculosis. There were no pathologic involvements except for the increased 18F-FDG uptake by the intrasellar lesion (Fig. 2). As the patient had no clinical signs or symptoms and no other findings on the imaging studies, active tuberculosis, sarcoidosis, and lymphoproliferative diseases were considered unlikely and a lumbar puncture was not performed.
Cranial images of 18F-FDG PET-CT. There is increased 18F-FDG uptake by the pituitary lesion.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-23-0125
When the various studies were completed, primary hypophysitis was considered the most likely diagnosis. Other sellar lesions, such as a germinoma, remained a possibility as a biopsy was not done.
Treatment
With the preliminary diagnosis of primary hypophysitis, the patient was started on glucocorticoid therapy because of the chiasmal compression and severe headaches. The starting dose of methylprednisolone was 80 mg/day. The dose was reduced by 8 mg per week until it reached 24 mg/day; then, a dose reduction of 4 mg every 2 weeks was applied. In the last 3 months, doses of 12 mg/day, 8 mg/day, and 6 mg/day were given, respectively. Treatment was discontinued at the end of the sixth month. Replacement therapies for central hypothyroidism and central hypogonadism were also prescribed and the doses adjusted accordingly during follow-up. Isoniazid prophylaxis (300 mg/day) was started along with glucocorticoid therapy.
Outcome and follow-up
One month after the start of methylprednisolone, the patient’s headaches completely subsided. There were some improvements in hormone deficiencies (data not shown), and the MRI obtained 7 weeks after the start of glucocorticoid treatment revealed a significant regression in the pituitary lesion (Fig. 3).
Pituitary MRI obtained 7 weeks after therapy was begun. The coronal (upper row) and sagittal (lower row) T2-weighted (A and D) and T1-weighted (unenhanced (B and E) and enhanced (C and F)) images show significant regression and a more homogeneous signal intensity and contrast enhancement of the gland. The thickening of the stalk and sphenoid sinus mucosa completely resolved. The dural thickening and contrast enhancement along the clivus persist.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-23-0125
Although severe headache, multiple pituitary hormone deficiencies, and MRI findings (increased stalk thickness, symmetrical enlargement, and contrast enhancement of the gland) were strongly suggestive of hypophysitis in the patient, there was still a possibility of other pituitary lesions such as germinomas. Regression of the mass following glucocorticoid therapy verified the diagnosis of hypophysitis.
The patient was re-evaluated 6 months after therapy began. All pituitary functions were restored, and all replacement therapies were discontinued at the seventh month (Table 1). The MRI findings were consistent with complete remission of the hypophysitis (Fig. 4). The process of the diagnosis and follow-up is summarized in Fig. 5.
Pituitary MRI obtained 6 months after therapy was begun. The coronal (upper row) and sagittal (lower row) T2-weighted (A and D) and T1-weighted (unenhanced (B and E) and enhanced (C and F)) images show regression in the dimensions of the gland with homogeneous signal intensity and contrast enhancement. The dural thickening and contrast enhancement along the clivus persist.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-23-0125
Algorithm summarizing the diagnostic process and management strategies of the presented case (Reference 1 was used as a guide).
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-23-0125
Discussion
The management of primary hypophysitis largely depends on the severity of the clinical picture and the compression of neural structures. Glucocorticoids are the first-line medical therapy, but the treatment responses are variable across studies. We present a patient with primary hypophysitis who had an excellent response to a single course of glucocorticoid therapy.
The symptomatology of patients with primary hypophysitis depends on the severity of the disease. The clinical presentation might be subtle in mild cases with no mass effect or may be debilitating with headaches, vision problems, cranial nerve paralysis, and symptoms associated with multiple pituitary hormone deficiencies in severe cases. Mild cases with presumable lymphocytic hypophysitis and no mass effects might be followed without interventions (1, 3). Honegger et al. reported spontaneous radiologic improvement in 46% and hormonal improvement in 27% of the patients who were clinically observed in their retrospective nationwide cohort (5). In severe cases with serious compression of neural structures, surgery might be the best option for fast decompression (1, 6). It was reported that surgery caused the most frequent radiologic improvement compared to other treatment options (7). However, pituitary dysfunction is high following surgery, and recurrences may still occur (5). Surgery should be considered for selected patients who are resistant to medical therapy and who have severe neurologic symptoms due to mass effect (6).
Immunosuppressants are the mainstay of medical treatment, with glucocorticoids being the first-line treatment in cases who are not suitable for clinical observation. Recent studies reported that improvement in pituitary functions and radiologic images was more frequent in patients treated with glucocorticoids compared to those observed without interventions (7, 8). Glucocorticoids have proven effective for the treatment of primary hypophysitis in many studies, and some case reports have presented complete improvement in radiologic findings resembling the presented case (6). However, the response rate following glucocorticoid therapy varies from 20% to 95% across studies (1). This might be explained by differences in patient populations, disease stages, dose and duration of steroid therapy, as well as different study designs.
Non-responsiveness and resistance to glucocorticoids have been the major problems during the management of patients with primary hypophysitis. The recurrence rate was 38% following glucocorticoid treatment after a mean of 0.5 years in one study (5). There have been attempts to analyze predictive factors for glucocorticoid responsiveness (8, 9, 10). Female gender and the presence of anti-pituitary antibodies were associated with better responses to immunosuppressive therapy (8, 9). The presence of diabetes insipidus was reported as a negative predictive factor (9, 10), while a prospective study reported the opposite (8). Lupi et al. observed better radiologic improvement in patients with panhypophysitis compared to those with infundibulo-neuro-hypophysitis (10). They stated that glucocorticoids may be effective for restoring anterior pituitary functions with no effects on the functions of the posterior pituitary (10). The chronicity of the disease is most probably another factor that determines responsiveness. Glucocorticoids are assumed to be more effective during the acute phase compared to the fibrotic chronic phase of the disease (1, 7). The successful response in our case might be explained by starting glucocorticoid therapy during the acute phase of the disease. Involvement only of the adenohypophysis seems to be another favorable factor. The patient most probably had lymphocytic (autoimmune) hypophysitis as it was accompanied by Hashimoto’s thyroiditis. Lymphocytic hypophysitis has been associated with a better steroid response compared to granulomatous and xanthomatous hypophysitis (11).
There is no consensus on the optimal type, dose, and duration of glucocorticoid therapy due to the rarity of the disease and thus lack of clinical trials. Some authors suggested high-dose regimens, but lower doses proved effective in mild-to-moderate cases too (8, 9). Table 2 summarizes the previous studies that specified the detailed tapering regime. The starting dose of methylprednisolone was 80 mg/day in the presented case, which was tapered by 8 mg per week during the first 2 months, then by 4 mg every 2 weeks until a dose of 12 mg/day was reached. A monthly dose reduction was applied, and the treatment was discontinued at the physiologic replacement dose at the end of the sixth month. This treatment protocol was effective for the patient who had a moderate severity of the disease. There is a paucity of studies directly comparing glucocorticoid dosing and weaning protocols. In a recent meta-analysis, Krishnappa et al. reported better responses in terms of improvement of the visual field defects and corticotroph axis dysfunctions in patients with severe disease after very high-dose glucocorticoids (>100 mg/day) and intravenous application compared to moderate doses (≤30 mg/day) and oral use (9). Moreover, a treatment duration of >6.5 weeks was associated with better hormonal improvement rates (9). The same research group reported the results of their retrospective study in which they compared the outcome of high-dose glucocorticoids (1 g/day intravenous methylprednisolone for 3 months followed by oral 60 mg/day methylprednisolone for 1 month, tapered over 5 weeks) and observation (12). There was a rapid improvement in cranial nerve palsies and visual field defects, and the improvement rates of anterior pituitary functions were better after glucocorticoids than observation (12). Another recent meta-analysis supports these results in terms of better improvement rates in anterior pituitary functions and radiologic appearances when supraphysiologic doses of glucocorticoids were applied as first-line treatment compared to observation (7). However, the glucocorticoid doses (from 10 mg/day to 1 g/day) and treatment duration varied greatly in the included studies (7). On the other hand, favorable results were reported with lower doses too. Chiloiro et al. applied prednisone at a dose of 50 mg/day for 3 months and then reduced the dose by 50% every 2 months. They prospectively compared the outcome with an observation group and reported better improvement rates in anterior pituitary functions in the glucocorticoid-treated group (8).
Glucocorticoid treatment regimens used in the patients with primary hypophysitis.
Reference | Patient characteristics | Glucocorticoid regimen | Comments regarding therapy response | |||
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n | Females, n | Age, years | Histologic subtype | |||
Kristof et al. (13) | 9 | 7 | 41 | Lymphocytic hypophysitis |
|
Improvement was observed in 44% of the patients in terms of pituitary functions and in 88% in terms of MRI findings. |
Khare et al. (14) | 4 | NS | 31.5 ± 9.57* | NS |
|
Regression of sellar lesion within 1 week of glucocorticoid therapy. |
Chiloiro et al. (8) | 12 | 9 | 42 (29) | Primary autoimmune hypophysitis |
|
Eight patients were responsive and four were resistant to the glucocorticoid therapy during second-year examination. |
Imga et al. (15) | 4 | NS | 44 (17-61)* | Lymphocytic (n = 3), NS (n = 1) |
|
Complete recovery in 1 patient. |
Korkmaz et al. (16) | 5 | 3 | 31 | Lymphocytic (n = 3), xanthomatous (n = 1), and primary hypophysitis (n = 1, clinically diagnosed) |
|
Pituitary functions improved in 1 and remained stable in 4. Radiologic regression was detected in 2, stability in 2, and progression in 1. |
Krishnappa et al. (12) | 18 | 14 | 36.4±14.6 | Primary autoimmune hypophysitis |
|
Improvement in pituitary functions was higher in glucocorticoid-treated patients than those observed. Radiological outcomes were similar in both groups. |
*The ages belong to the whole cohort included in the study. The age of the patients who received glucocorticoids was not specified.
NS, not specified.
This case report contributes to the literature as an excellent response to a single course of glucocorticoids. Clinical observation and glucocorticoid therapy are two treatment strategies that should be individually decided upon. Keeping in mind the potential adverse effects of glucocorticoids, they should be started in patients with a more severe disease course. Glucocorticoid therapy may have very satisfying results in selected cases. Recurrences should be kept in mind, and the patients should be closely followed after therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Patient consent
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient.
Author contribution statement
All authors made individual contributions to authorship; AH: involved in manuscript writing and submission; GE, UT, and FK: involved in the diagnosis and management of the patient; GE: preparation of radiology images; ZK, FK: involved in submission and supervision. All authors reviewed and approved the final draft.
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