Adult Workshop 1 HORMONE Horm Res 2007;68(suppl 5):145–150 Published online: December 10, 2007 RESEARCH DOI: 10.1159/000110611 Lymphocytic Hypophysitis Mark E. Molitch Mary P. Gillam Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill. , USA Key Words cated as a means of attenuating inflammation, but given the ,Lymphocytic hypophysitis ؒ Sellar mass ؒ Hypopituitarism ؒ uncertainty of its efficacy and the known adverse effects Pregnancy such therapy does not seem justified for most patients. The optimal surgical strategy involves partial resection of the mass to decompress the surrounding structures. All patients Abstract with lymphocytic hypophysitis require appropriate replace- Background: Lymphocytic hypophysitis is a disorder of the ment therapy for deficient hormones. Long-term follow-up pituitary gland that presents as a sellar mass lesion and/or is mandatory to monitor for the development of other hor- hypopituitarism. It causes pituicyte destruction and hypopi- monal deficits. Copyright © 2007 S. Karger AG, Basel tuitarism and is speculated to have an autoimmune basis. Diagnosis: Lymphocytic hypophysitis should be considered in the differential diagnosis of pituitary masses and/or hypo- pituitarism in females who are pregnant or in the early post- Introduction partum period, especially in cases associated with other autoimmune diseases or unusual patterns of hormone defi- Lymphocytic hypophysitis is an unusual disorder of ciencies. A definitive diagnosis requires tissue biopsy. A pre- the pituitary gland that presents as a sellar mass lesion sumptive clinical diagnosis can be made based on a history and/or hypopituitarism, most often associated with preg- of gestational or postpartum hypopituitarism, a contrast-en- nancy and the postpartum period. Since the original de- hancing sellar mass with imaging features characteristic of scription by Goudie and Pinkerton [1] , almost 400 cases lymphocytic hypophysitis, a pattern of pituitary hormone of biopsy-proven lymphocytic hypophysitis have been re- deficiency with early loss of adrenocorticotrophic hormone ported [2–5] . The true incidence of lymphocytic hypoph- and thyroid-stimulating hormone unlike that typically found ysitis is unknown as it is likely to be underestimated due with macroadenomas, relatively rapid development of hy- to confusion with Sheehan syndrome and spontaneous popituitarism and a degree of pituitary failure dispropor- recovery of undiagnosed cases. The earliest descriptions tionate to the size of the mass. Symptoms resulting from par- of lymphocytic hypophysitis emphasized its exclusive as- tial or panhypopituitarism occur in approximately 80% of sociation with pregnancy and the postpartum period. cases and multiple deficiencies are found in approximately However, cases have also been reported both in men and 75% of cases. Management: Appropriate management re- in women having no relationship to pregnancy. mains controversial. Corticosteroid therapy has been advo- © 2007 S. Karger AG, Basel Mark Molitch, MD 0301–0163/07/6811–0145$23.50/0 Northwestern University Medical School (Tarry 15-731) Fax +41 61 306 12 34 Center for Endocrinology, Metabolism and Molecular Medicine E-Mail [email protected] Accessible online at: 303 E. Chicago Avenue, Chicago, IL 60611 (USA) www.karger.com www.karger.com/hre Tel. +1 312 503 4130, Fax +1 312 908 9032, E-Mail [email protected] Classification and Pathology Pathogenesis Hypophysitis may be classified by its anatomic distri- The etiology of lymphocytic hypophysitis is unknown, bution and whether it is a primary or secondary finding. but it has been speculated to have an autoimmune basis With respect to anatomic classification, the most com- [2–5, 9] . Nearly 30% of patients have a history of coexist- mon form of lymphocytic hypophysitis is confined to the ing autoimmune diseases such as Hashimoto thyroiditis, anterior pituitary and causes pituicyte destruction and Addison disease, type 1 diabetes and pernicious anemia hypopituitarism; diabetes insipidus (DI) is uncommon [2–5, 7] , and the condition is now considered a compo- [2–5] . Much less commonly, hypophysitis may primarily nent of the type 1 polyglandular syndrome [2–5, 14] . The involve the infundibulum and posterior pituitary, caus- epidemiologic association of lymphocytic hypophysitis ing DI and hyperprolactinemia from stalk dysfunction; with pregnancy has been proposed as circumstantial ev- however, anterior pituitary function is usually preserved idence supporting an autoimmune pathogenesis [15, 16] . [2–6] . Lymphocytic infundibulo-panhypophysitis is even Limited experimental animal studies have supported more rare, with lymphocytic infiltration and destruction the autoimmune theory of lymphocytic hypophysitis present in both the anterior and posterior pituitary. These with hypophyseal infiltrates developing after injections patients present with a combination of DI and anterior of pituitary extracts [17–20] . However, the pathology in pituitary deficiency [2–5] . these experimental conditions does not exactly mimic There are three primary forms of hypophysitis: lym- that seen in humans [3] . phocytic, granulomatous and xanthomatous. Lympho- Although antipituitary antibodies have been demon- cytic hypophysitis is characterized by dense lymphocytic strated in some patients with lymphocytic hypophysitis, infiltration of the anterior pituitary and destruction of their specificity for hypophysitis is poor, as they are also the normal pituitary architecture and replacement with present in patients with nonautoimmune pituitary dis- fibrosis [2–5, 7, 8] . Some studies have shown that the lym- ease and other nonpituitary autoimmune disease [15, 21– phocytes are predominantly cytotoxic T-lymphocyte 24] and in normal postpartum women who do not de- (CD8+) cells, suggesting that T cell-mediated cytotoxic- velop hypophysitis [25] . Taken together, the preponder- ity is critical in the pathogenesis of the disorder [9] . Gran- ance of evidence supports an autoimmune basis, but this ulomas and multinucleated giant cells are not found in remains to be proved. lymphocytic hypophysitis and, if observed, suggest an alternative diagnosis of granulomatous hypophysitis, which is a much rarer disorder occurring at an incidence P r e s e n t a t i o n of ! 1/1,000,000. Granulomatous hypophysitis occurs in men and women with equal frequency and is not particu- When associated with pregnancy, lymphocytic hy- larly associated with pregnancy. It also presents as a mass pophysitis typically presents in the third trimester of lesion with hypopituitarism and is characterized by giant pregnancy or within 1 year postpartum, with symptoms cell granulomas [2–5, 7, 9] . The final major variant is xan- usually related to a pituitary mass (headaches or visual thomatous hypophysitis, of which less than a dozen cases symptoms) or hypopituitarism ( table 1 ). The disorder is have been reported. The pathology of xanthomatous hy- often brought to attention due to failure of either lacta- pophysitis is characterized by a predominance of foamy tion or menses following delivery [2–5, 26] . Neurohypo- macrophages, some lymphocytes and single plasma cells physial involvement, manifesting as DI, occurs in 15% of [3, 9] . Other more rare types of hypophysitis appear to be cases [2–5, 7, 26] . Other rare presentations of lympho- part of a more generalized inflammatory process and in- cytic hypophysitis include meningeal irritation [27] , dip- clude Rosai-Dorfman disease [10] and fibrosing inflam- lopia due to cavernous sinus involvement [27] and occlu- matory pseudotumor (also called Tolosa-Hunt syndrome sion of the internal carotid arteries [28] . and parasellar chronic inflammatory disease) [11–13] . Symptoms resulting from partial or panhypopituita- Although hypophysitis is usually thought of as a pri- rism occur in approximately 80% of cases [2–5, 7, 26] , and mary process, it may occur secondarily in relation to in- multiple deficiencies are found in approximately 75% of fection (viral, bacterial, fungal, tuberculosis, syphilis) or cases [2–5, 7, 26] . There is an inexplicable unique predilec- other processes such as Langerhans cell histiocytosis, tion for the corticotrophs and thyrotrophs to be affected sarcoidosis, Wegener granulomatosus, Crohn disease, while the gonadotrophs may be spared. Prolactin levels Takayasu disease and ruptured cysts [2–5] . range from unmeasurable to elevated: low levels are at- 146 Horm Res 2007;68(suppl 5):145–150 Molitch/Gillam Table 1. Lymphocytic hypophysitis: clinical symptoms at presen- acteristics distinguish hypophysitis from a macroade- tation noma ( table 2 ). With hypophysitis, the gland is gener- ally symmetrically enlarged, and administration of gad- Symptoms Frequency, % olinium homogeneously enhances the gland. By contrast, Mass effects in adenomas gadolinium enhances the gland more fo- Headache 60 cally. In lymphocytic hypophysitis, the pituitary dis- Visual disturbance 40 plays a relative low signal on T1 - and a relatively high Bitemporal hemianopsia 32 signal on T -weighted images. By comparison, in mac- Impaired visual acuity 2 Diplopia <5 roadenomas a low signal on T1 -weighted images is un- common, but a high signal on T2 -weighted images is oc- Endocrine dysfunction 80 casionally seen [32] . Often, the dura mater adjacent to Adrenal insufficiency 65 Hypothyroidism 60 the mass in lymphocytic hypophysitis shows a unique, Growth hormone deficiency 54 marked contrast