Hypophysitis is an inflammation of your pituitary gland, presenting as varying degrees of endocrine failure. It’s a rare disorder, affecting 1 in 9 million people, especially females during pregnancy or after childbirth. However, newer data suggest underdiagnosis, especially in peripartum women.[1]
Hypophysitis is a less-known and often overlooked disease that may result in permanent hormonal issues, vision problems, maternal complications, and infertility. Clinicians need to understand it to help catch more cases and improve patient outcomes through timely and targeted treatment.
Understanding the Pathophysiology
What is the Pituitary Gland?
The pituitary is a pea-sized gland located in the Sella Turcica of the sphenoid bone in your skull. It’s divided into an anterior lobe and a posterior lobe. The anterior lobe influences the growth, metabolism, thyroid, adrenal, and reproductive function in your body through its respective hormones, such as Thyroid Stimulating Hormone (TSH) or Adrenocorticotropic Hormone (ACTH). The posterior lobe is involved with regulating water balance via its hormones. Both these lobes work under the influence of the hypothalamus.
Anatomy of the pituitary gland (Image credits: freepik)
What happens to the Pituitary in Hypophysitis?
In hypophysitis, when inflammatory infiltrates invade and damage your pituitary, all these functions are partially or completely lost. The resulting manifestations depend upon which lobe is affected and how much.
Also, this damage causes your gland to swell, pushing nearby structures and producing corresponding symptoms. For example, the visual disturbances result from the pituitary’s compression upon the adjacent optic chiasm.
What causes Hypophysitis?
The main causes of hypophysitis include:
- Autoimmune: A derangement of our immune system causes T-cells to attack the pituitary gland. Some scientists also believe that certain autoantibodies, such as anti-Pit-1 and anti-rabphilin-3A, may be involved, although these tests are not widely available or standardized.[2]
- Pregnancy or Postpartum: The physiological enlargement of the pituitary during pregnancy or after birth, and the immune shifts, make women more vulnerable to the lymphocytic variant of hypophysitis.[3]
- Immune Checkpoint Inhibitors (ICIs): Used to treat cancers, these drugs block various checkpoints in your body’s immune pathways, enhancing the overall immune response. While this hyperactive immune response helps the body fight cancer cells, at the same time, it may attack our organs too. Scientists label these effects as Immune-related Adverse Events (irAEs), which also include hypophysitis. Examples of ICIs include ipilimumab (anti-CTLA-4) and pembrolizumab (anti-PD-1).4Tang, Qirui MMa; Han, Yaru MMb; Song, Min MMc; Peng, Jing MMd; Zhang, Mei MMc; Ren, Xiaolei MDe; Sun, Hailing MMc,*. The association of hypophysitis with immune checkpoint inhibitors use: Gaining insight through the FDA pharmacovigilance database. Medicine 103(13):p e37587, March 29, 2024. | DOI: 10.1097/MD.0000000000037587
- Systemic inflammatory diseases: Sarcoidosis and IgG4-related disease can secondarily involve the pituitary and mimic primary hypophysitis.
Types of Hypophysitis
Hypophysitis can either be primary, i.e, due to a problem with the pituitary itself, or it can be secondary, i.e, due to an issue elsewhere in the body:
Primary Hypophysitis:
Primary hypophysitis is idiopathic. Scientists attribute it to a derangement of our immune system, in which our cells start attacking the pituitary gland, causing inflammation and subsequent symptoms. Based on histopathology, it’s further categorized into the following subtypes:
- Lymphocytic: It’s the most common one, with predominance of lymphocytes in the pituitary lesion.[4]. Pregnancy and postpartum causes are strongly linked to it.
- Granulomatous: There is the presence of giant cells, histiocytes, and granulomas in this subtype.
- Xanthomatous: This type has lipid-laden macrophages in the absence of granulomas.
- IgG4-related: The hallmark is the presence of plasma cells and strong IgG4 positivity.
- Necrotizing: This type is the least common and is marked by necrosis surrounding the inflammatory cells.
Secondary Hypophysitis:
This may arise secondary to:
- Infections: These include bacterial infections such as Tuberculosis, Syphilis, granulomatous diseases like sarcoidosis, etc, as well as some viral illnesses. The manifestations in these cases often show hypopituitarism.
- Drug-induced: Drugs, particularly the Immune Checkpoint Inhibitors, are notorious for causing hypophysitis. The deficiency of the adrenal hormone is more pronounced in these patients, putting them at risk of unrecognized, life-threatening adrenal crisis.
- Sellar lesions, such as a germinoma, Rathke’s cyst, or Pituitary Adenoma, may also increase one’s probability of getting hypophysitis.
- Immunoglobulin-related disease: Hypophysitis can also occur as part of systemic conditions such as IgG4-related disease.
Symptoms of Hypophysitis
The clinical features of hypophysitis vary from patient to patient depending upon the anatomical location of the lesion and the etiology.
Mass Effects:
These include:
- Headache: Often a dull, persistent one, felt on the forehead or behind the eyes.
- Visual defects: Such as blurred vision, double vision, or tunnel vision
These symptoms are quite common and arise due to the pressure effects of the enlarged pituitary upon the surrounding structures.
Deficiencies of the Anterior Pituitary:
Central Adrenal Insufficiency
A deficiency of Adrenocorticotropic Hormone (ACTH) causes a decline in the adrenal hormone cortisol, producing the following symptoms:
- Fatigue
- Weight loss
- Low blood pressure
- Abdominal pain, nausea
If left untreated, it can quickly progress to adrenal crisis (also known as acute adrenal insufficiency) – a medical emergency.
Central Hypothyroidism
This results from low free thyroxine (fT4) with a low or inappropriately normal TSH, and manifests as:
- Inability to tolerate cold
- Weight gain
- Dry skin
- Constipation
- Slugginess
Effects on Reproductive Organs
Arising secondary to a deficiency of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), these manifest differently in respective genders, for example:
- Women may present with amenorrhea, irregular periods, or infertility
- Men may have erectile dysfunction, a decreased libido, or reduced muscle mass
Growth Hormone (GH) Deficiency
- Children present with poor growth and/or delayed puberty
- Adults present with fatigue, emotional instability, increased fat, or poor muscle tone.
Effect on Prolactin Secretion
Depending upon where the lesion is, there may be a hypo- or hypersecretion of the Prolactin hormone.
- Hyperprolactinemia is usually mild (<150 ng/mL) in stalk-involved hypophysitis. Patients may develop menstrual irregularities, galactorrhea (milky nipple discharge), or infertility. Levels >200 ng/mL suggest prolactinomas instead.
- Hypoprolactinemia, though less common, can manifest as failure to lactate after childbirth.
Deficiencies of the Posterior Pituitary Hormones:
Hypophysitis affects the secretion of Vasopressin (also known as the Antidiuretic Hormone), causing Diabetes Insipidus. Its characteristic symptoms are:
- Polyuria: Passing too much urine
- Polydipsia: Feeling intense thirst
- Nocturia: Night-awakening to pass urine
- Dehydration
How to diagnose Hypophysitis?
Hypophysitis is a diagnosis of exclusion. Doctors correlate your clinical picture, hormonal profile, and imaging to rule out the differentials and confirm the diagnosis.
Clinical Evaluation:
Your doctor will obtain a thorough medical history. He may specifically want to know if:
- You are pregnant
- Have any signs of a systemic or autoimmune disease
- Show symptoms of hypopituitarism
Then, he may proceed to assess your full hormonal profile.
Hormonal Profile:
Since hypophysitis often presents with a decline in pituitary hormones, your healthcare provider may ask you to get these tests done:
- Serum cortisol and adrenocorticotropic hormone (ACTH): Both are typically low or inappropriately normal, suggesting central adrenal insufficiency.
- Thyroid Stimulating Hormone (TSH) and Free Thyroxine: Low free T4 with low/normal TSH confirms central hypothyroidism.
- Luteinizing hormone (LH), Follicular Stimulating Hormone (FSH), and sex hormones: These hormones also show a decline, helping identify hypogonadotropic hypogonadism.
- Serum Prolactin: It may either be low due to a pituitary lesion or mildly elevated due to the stalk effect (<150 ng/mL). An elevation of >200 ng/mL favours prolactinomas instead.
- Insulin-like Growth Factor-1: Doctors use it to screen for deficiency of the growth hormone (GH)
- Serum Electrolytes (Sodium, Potassium), serum & urine osmolality: To check for diabetes insipidus
- Labs for Antidiuretic hormone are rare due to technical difficulties.
- Pituitary Autoantibody testing may be recommended if a relevant facility is available
Magnetic Resonance Imaging (MRI):
MRI with gadolinium contrast is the investigation of choice for non-pregnant patients. It visualizes the pituitary gland, helping identify these findings:[5]
- Symmetrical enlargement of the pituitary gland
- Homogeneous contrast enhancement after gadolinium administration
- Thickened and straightened pituitary stalk
- Loss of the “posterior pituitary bright spot” on T1-weighted images (if diabetes insipidus is present)
- Glands may appear dumbbell-shaped or triangular, in contrast to rounder adenomas
- Intact sellar floor, suggesting inflammation rather than a neoplasm
- “Dark T2 signal” in parasellar regions (a rare but suggestive sign of lymphocytic infiltration)
MRI showing pituitary gland enlargement and enhancement consistent with hypophysitis. Image courtesy: Wilson MA, Guld K, Galetta S, Walsh RD, Kharlip J, Tamhankar M, McGettigan S, Schuchter LM, Fecher LA.Acute visual loss after ipilimumab treatment for metastatic melanoma.Case Rep Oncol Med. 2016;2016:9058980. doi:10.1155/2016/9058980. Under CC license
Difference between Hypophysitis & Pituitary Adenoma MRI
| Feature | Hypophysitis | Pituitary Adenoma |
|---|---|---|
| Enhancement | Uniform | Often heterogeneous |
| Stalk involvement | Thickened and midline | Often displaced |
| Posterior bright spot | May be lost | Typically retained |
| Symmetry | Symmetrical | Asymmetrical/mass effect |
| Sellar erosion | Usually absent | Can be present |
(Note: Gadolinium is considered unsafe in pregnancy, especially in the first trimester. Therefore, MRI without gadolinium is preferred in pregnant patients.)
Pituitary Autoantibody Testing:
Tests for autoantibodies such as Anti–Pit-1, anti-rabphilin-3A do exist, and help differentiate autoimmune-related hypophysitis from tumor-related cases. However, they aren’t readily available, nor are they yet standardized.
Pituitary Biopsy:
It’s the gold standard investigation for primary hypophysitis. But since it’s invasive, doctors rarely perform it. In fact, they reserve a biopsy for cases with diagnostic uncertainty or treatment resistance. In hypophysitis, a pituitary biopsy would reveal:
- Dense T-cells and/or fibrosis in lymphocytic hypophysitis
- Granulomas, giant cells, and lipid-laden macrophages in granulomatous and xanthomatous subtypes, respectively.
- Necrosis around lymphocytes in necrotizing hypophysitis
- IgG-4 positive plasma cells in the IgG-related subtype
Other investigations:
These include labs to look for any underlying systemic diseases:
- Tuberculosis workup: Chest X-ray, interferon gamma release assay (IGRA), sputum for Acid Fast Bacilli
- Sarcoidosis markers: Angiotensin converting enzyme (ACE) levels, chest CT
- IgG4-related disease panel: Serum IgG4 levels, salivary gland ultrasound, pancreas imaging
- Cancer screening: If the patient is on immune checkpoint inhibitors, assess for metastases or paraneoplastic syndromes
Treatment of Hypophysitis
In the treatment of hypophysitis, doctors focus on replacing the hormones and preventing complications.[6]
Hormone Replacement Therapy:
It’s the treatment of choice for mild cases of hypophysitis and pregnancy-induced ones. Depending upon your symptoms and lab reports, your doctor may prescribe:
- Levothyroxine for central hypothyroidism
- Glucocorticoids for central adrenal insufficiency
- Estrogen, Progestin, or Testosterone for the deficiency of gonadotropins
- Desmopressin, in case Diabetes Insipidus is present
Glucocorticoid Therapy:
For moderate to severe cases, especially those with severe compression effects, doctors consider glucocorticoids. These help reduce inflammation and also ease the pressure effects on surrounding structures. Commonly prescribed are Prednisone and Hydrocortisone, and the typical starting dose is 1mg/kg/day. Glucocorticoids have been shown to shrink the gland in the majority of cases, with around 50% recovery of the pituitary function.
Also, a recent meta-analysis concluded that administering higher doses of intravenous glucocorticoids for longer periods produces better outcomes.[7]
Immunosuppressive Agents:
These are drugs that inhibit your immune response and are reserved for steroid-refractory cases. The popular ones include:
- Methotrexate
- Azathioprine
- Cyclosporin A
- Rituximab
Surgery:
Doctors may consider surgery or radiotherapy when your vision loss rapidly progresses, or when doctors aren’t sure if it’s an inflammation of the pituitary or a tumor. The regular route that surgeons follow is transsphenoidal, with resolution of symptoms in 70% of the cases.
Differential diagnosis
Doctors rule out these conditions to diagnose hypophysitis:
- Pituitary Adenoma: It’s a benign tumor of the pituitary gland that may cause compression effects or hypersecretion of the pituitary hormones. Its characteristic MRI findings help differentiate it from hypophysitis.
- Pituitary Apoplexy: it’s a condition of acute hemorrhage or infarction in a pre-existing pituitary tumor. The symptoms include a sudden, severe headache, vision loss, and/or an altered mental status. Doctors usually diagnose it based on an MRI, which shows hemorrhage and fluid-fluid levels in the pituitary tissue.
- Rathke’s Cleft Cyst: It’s a benign, fluid-filled pouch located between the two lobes of the pituitary. MRI shows a well-circumcised, cystic lesion in the Rathke’s pouch.
- Craniopharyngioma: It’s a benign tumor originating in the Rathke’s pouch. Characteristic findings on an MRI include calcifications, suprasellar extension, and cystic-solid components.
- Langerhans’ Cell Histiocytosis (LCH): It’s a rare systemic disease causing multi-organ damage, arising due to the proliferation of Langerhans-type dendritic cells. It’s diagnosed through a skin and/or bone biopsy.
- Germinoma: It’s a germ cell tumor that commonly affects children and teenagers. Characteristic findings include elevated tumor markers and a solid enhancing mass on an MRI. Diagnosis is confirmed through a CSF or a skin biopsy.
- Sarcoidosis: It’s a multisystem granulomatous disease that can affect your nervous system, too. While MRI findings may overlap with hypophysitis, doctors differentiate it on the basis of an elevated ACE level, characteristic findings on peripheral lesions’ biopsy, and chest CT.
- Tuberculosis of the pituitary: it’s a very uncommon presentation of CNS tuberculosis. Doctors differentiate it from hypophysitis through a positive TB history or travel to endemic areas, caseating granulomas on MRI, and standard TB tests such as the IGRA, sputum for AFB, and a CSF PCR.
Can you get Hypophysitis in Pregnancy?
Yes. While stats say it’s rare in pregnancy, a lot of scientists believe that the low numbers are because it often goes unrecognized. Out of the reported cases, 70-80% occur soon after birth, whereas the remainder emerge in the third trimester.
Pathophysiology:
During pregnancy, our immune response is kind of tapered to accommodate the new life inside us. But once the baby is born, this suppressed immunity shoots up, producing an exaggerated immune response that, at times, may attack our own body, including the pituitary gland. Scientists also believe that the physiological increase in pituitary size during pregnancy makes it more vulnerable to immune attacks.
Symptoms:
The symptoms of hypophysitis in pregnancy resemble the regular postpartum signs, which is one reason why it gets overlooked in women:
- Headache
- Visual defects
- Lactation failure or amenorrhea
- Fatigue, nausea, and dizziness secondary to adrenal insufficiency
- Since the posterior pituitary is usually spared, affected females do not present with symptoms of diabetes insipidus
How is it diagnosed?
MRI is the investigation of choice. It yields the same findings as in the non-pregnant patients, except that it’s done without contrast in pregnancy due to the safety profile of gadolinium. Moreover, the loss of the posterior pituitary bright spot is less common, as hypophysitis in pregnancy doesn’t involve the posterior lobe.
Treatment:
Most cases resolve smoothly if diagnosed and treated in time. Doctors start the treatment with low-dose corticosteroids and hormone replacement therapy. Surgery isn’t usually required, except when there are mass effects or when doctors strongly suspect pituitary tumors or masses. Prognosis is quite positive with a total or partial resumption of pituitary function and restoration of fertility in most cases.[8]
Complications of Hypophysitis
The complications of hypophysitis include:
- Adrenal Crisis: It’s a life-threatening complication that occurs due to a deficiency of cortisol. Stress, infection, or surgery might precipitate it. The common symptoms are hypotension, vomiting, confusion, and shock. Remember, it’s a medical emergency and requires urgent intravenous hydrocortisone and fluid support.
- Permanent Hypopituitarism: It’s an irreversible failure of the pituitary function that requires lifelong hormonal replacement therapy.
- Vision Loss: The compression of the optic chiasm by the enlarged pituitary sometimes manifests as vision loss. It’s temporary but may become permanent if not treated in time.
- Relapse: It may occur in pregnancy-related or ICI-induced hypophysitis. This is why the importance of regular follow-ups cannot be overemphasized
- Empty Sellar Syndrome: It’s a syndrome in which your pituitary may shrink or flatten against the sella turcica, often secondary to long-standing inflammation.
- Fertility issues: Due to a deficiency of sex hormones, patients may face difficulty getting pregnant. It’s manageable with adequate hormone replacement and regular follow-ups.
Prognosis of Hypophysitis
Hypophysitis shows varying outcomes, depending upon the etiology and timeliness of treatment.
- Around half of the patients recover spontaneously, without steroids, whereas others may develop persistent hypophysitis and require lifelong hormonal support.
- Mortality occurs in 6-7% of the cases, and is mainly attributed to adrenal crisis or misdiagnosis.[9]
- Since relapses and permanent defects aren’t uncommon, doctors usually recommend regular follow-ups every 3-6 months to track progression, hormone function recovery, and relapses.
Conclusion
Hypophysitis is an inflammatory disorder of the pituitary gland that presents with mass effects and hormonal deficiencies. Diagnosis depends on clinical evaluation, hormonal profile, and characteristic MRI findings. Treatment primarily involves conservative management and hormone replacement, and may extend to surgery or immunosuppressants for severe cases. Prognosis is favourable, especially with an early diagnosis and timely treatment. This is why the importance of early detection and management cannot be overemphasized.
References
[1] Langlois, F., Varlamov, E. V., & Fleseriu, M. (2021).Hypophysitis, the growing spectrum of a rare pituitary disease.The Journal of Clinical Endocrinology & Metabolism, 107(1), 10-28. doi:10.1210/clinem/dgab672 — this review says “previously reported estimates are 1/9 million” but cautions that the true incidence is unknown and probably higher.
[2] Iwama, S., Sugimura, Y., Kiyota, A., Kato, T., Enomoto, A., Suzuki, H., Iwata, N., Takeuchi, S., Nakashima, K., Takagi, H., Izumida, H., Ochiai, H., Fujisawa, H., Suga, H., Arima, H., Shimoyama, Y., Takahashi, M., Nishioka, H., Ishikawa, S. E., Shimatsu, A., … Oiso, Y. (2015). Rabphilin-3A as a Targeted Autoantigen in Lymphocytic Infundibulo-neurohypophysitis.The Journal of clinical endocrinology and metabolism,100(7), E946–E954.
[3] Caturegli, P., Newschaffer, C., Olivi, A., Pomper, M. G., Burger, P. C., & Rose, N. R. (2005). Autoimmune hypophysitis.Endocrine reviews,26(5), 599–614.
[4] Tang, Qirui MMa; Han, Yaru MMb; Song, Min MMc; Peng, Jing MMd; Zhang, Mei MMc; Ren, Xiaolei MDe; Sun, Hailing MMc,*. The association of hypophysitis with immune checkpoint inhibitors use: Gaining insight through the FDA pharmacovigilance database. Medicine 103(13):p e37587, March 29, 2024. | DOI: 10.1097/MD.0000000000037587
[5] Honegger, J., Giese, S., Nasi-Kordhishti, I., & Donegan, D. M. (2023). Pregnancy-related hypophysitis revisited.European journal of endocrinology,188(2), lvad003.
[6] Ju, J., Cui, T., Zhao, J., Chen, J., Ju, H. (2023). Clinical presentation and magnetic resonance imaging characteristics of lymphocytic hypophysitis: a systematic review with meta-analysis. Archives of Medical Science, 19(4), 976-986.
[7] RE. Hypopituitarism: Emergencies. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA)2000.
[8] Krishnappa, B., Shah, R., Memon, S. S., Diwaker, C., Lila, A. R., Patil, V. A., Shah, N. S., & Bandgar, T. R. (2022). Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis. Endocrine Connections, 12(2).
[9] Honegger, J., Giese, S., Nasi-Kordhishti, I., & Donegan, D. M. (2023). Pregnancy-related hypophysitis revisited. European journal of endocrinology, 188(2), lvad003.
[10] Prete A, Salvatori R. Hypophysitis. [Updated 2021 Oct 15]. In: Feingold KR, Ahmed SF, Anawalt B, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519842/