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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 9 4137-4141
Copyright © 2002 by The Endocrine Society

Original Article

Pituitary Autoimmunity in Patients with Sheehan’s Syndrome

Ravinder Goswami, Narayana Kochupillai, Patricia A. Crock, Abdul Jaleel and Nandita Gupta

Department of Endocrinology and Metabolism and Diabetes (R.G., N.K., A.J., N.G.), All India Institute of Medical Sciences, New Delhi 110029, India; and Paediatric Endocrine Unit (P.A.C.), John Hunter Children’s Hospital, University of Newcastle, Newcastle, New South Wales 2310, Australia

Address all correspondence and requests for reprints to: Prof. N. Kochupillai, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail: . kochupillai{at}hotmail.com

Abstract

Postpartum hemorrhage (PPH) is a frequent complication of pregnancy in India. Sheehan’s description of postpartum hypopituitarism promoted the belief that PPH leads to necrosis of the enlarged pituitary gland of pregnancy and hypopituitarism. However, slow clinical progression suggests factors other than ischemia in its pathogenesis. Tissue necrosis could release sequestered antigens, triggering autoimmunity of the pituitary and delayed hypopituitarism in Sheehan’s syndrome. Twenty-six consecutive patients with postpartum hypopituitarism were studied, 19 with Sheehan’s syndrome based on a history of PPH and hormone profile suggesting pituitary failure [mean (SD) age 32.7 ± 6.4 yr, duration of illness 5.5 ± 3.1 yr], and seven patients with no history of PPH, categorized as "Other." Pituitary imaging and basal T4, TSH, cortisol, LH, FSH, 17ß-estradiol, and autoantibodies against pituitary (PitAb) and thyroid (TMA) were evaluated. Controls included 28 healthy females without prior conception (22 ± 5 yr) and 28 with prior conception (26 ± 5 yr). Twelve of 19 (63.1%) patients with Sheehan’s syndrome and one of seven in the Other group had PitAb against the 49-kDa autoantigen; neuron-specific enolase. Four of 28 (14.2%) controls without prior conception and 5 of 28 (17.8%) controls with prior conception had PitAb positivity (P < 0.001 and <0.01 vs. Sheehan’s syndrome, respectively). There was no significant difference in the mean serum hormone values and TMA positivity between patients with Sheehan’s syndrome and the Other group as well as patients with or without PitAb positivity. Pituitary autoimmunity may play a role in the cause of hypopituitarism following PPH.

SHEEHAN (1), IN 1937, described the syndrome of postpartum hemorrhage (PPH), pituitary necrosis, lactation failure, and hypopituitarism. With better obstetric care, such complications of pregnancy are rare in the industrialized countries of the West. The National Family Health Survey in India (1998–1999) revealed 66% of childbirths to be home deliveries (2). The prevalence of anemia in pregnancy (<10.9%) in the country is 49.7%, the incidence of PPH 11%, and maternal mortality 428–653/105 live births (2). These data make it likely that postpartum pituitary failure is common in India. However, clinically, such patients often present late with severe hypopituitarism and circulatory collapse (3, 4, 5). Sheehan’s description of the syndrome promoted the belief that PPH leads to necrosis of the hyperplastic pituitary gland of pregnancy with resultant hypopituitarism and failure of lactation (1, 6). Release of sequestered pituitary antigens from necrotic pituitary tissue with the subsequent triggering of pituitary autoimmunity could lead to postpartum hypopituitarism in such cases. Recently autoantibodies against a 49-kDa pituitary cytosolic protein, identified as neuron-specific enolase, have been reported in patients with autoimmune lymphocytic hypophysitis (7, 8, 9, 10). Using the above autoantibody as a marker, we report results that demonstrate pituitary autoimmunity among patients with Sheehan’s syndrome.

Materials and Methods

Twenty-six consecutive patients with the onset of postpartum hypopituitarism followed up in the endocrine clinic of All India Institute of Medical Sciences (AIIMS), Delhi, during 1998–2000 were studied. Nineteen patients had Sheehan’s syndrome based on a history of PPH along with a clinical picture and hormone profile suggesting pituitary failure. Seven patients without a history of PPH were categorized as "Other" because hypopituitarism in them might have been due to antepartum hemorrhage, lymphocytic hypophysitis, idiopathic empty sella, or other causes (Tables 1GoGo and 2Go). Clinical features included imaging of the pituitary and pituitary function as assessed by basal serum total T4, TSH, cortisol (0800 h), LH, FSH, 17ß-estradiol measurements using commercial kits for LH, FSH, T4, and TSH (Medicorp Inc., Montreal, Quebec, Canada), 17ß-estradiol (DiaSorin, Inc., Saluggia, Vercelli, Italy), and cortisol (Immunotech, Marseille, France). All hormone assays were batched together. Intraassay coefficient of variation ranged from 4.0% to 7.2% for these hormones. The normal basal ranges in our laboratory are 52–167 nmol/liter for serum T4, 0.3–4.0 mU/liter for TSH, 260–720 nmol/liter for cortisol, 0.5–15 IU/liter for LH, 0.2–10 IU/liter for FSH, and 110–734 pmol/liter for 17ß-estradiol. Informed consent was obtained from all subjects, and the study was approved by the Research Committee of the AIIMS, New Delhi. Clinical features recorded include details of the last childbirth, PPH, blood transfusion, lactation failure, amenorrhea, and neonatal outcome. T1- and T2-weighted magnetic resonance imaging was done in 24 patients and computed tomography in two patients. A basal blood sample was drawn from each patient and sera were preserved in multiple aliquots at -20 C for pituitary (PitAb) and thyroid microsomal autoantibody (TMA) assays. Controls included 28 healthy females with no prior history of conception (mean age 22 ± 5 yr) and 28 healthy females with prior conception and normal obstetric history (mean age of 26 ± 5 yr) who were 4 ± 2 yr postpartum.


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  		Table 1. Clinical and pituitary autoantibody positivity data in patients with Sheehan’s syndrome (n = 19) and "Other" with postpartum hypopituitarism (n = 7)

 

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  		Table 1A. Continued

 

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  		Table 2. Clinical characteristics, PitAb positivity, hormone profile, and imaging findings among patients with Sheehan’s syndrome and "Other" group

 
PitAb was assayed using Western blot analysis as described previously (7, 11, 12). Briefly, a total of 10 normal human pituitaries, obtained at autopsy, 4–8 h postmortem, and frozen at -70 C were homogenized in PBS with protease inhibitors. The cytosol fraction was depleted of IgG with protein-A Sepharose (Amersham-Pharmacia Biotech, Uppsala, Sweden) and stored in aliquots at -70 C. Cytosol fractions were boiled for 2 min in the presence of 1,4-dithiothreitol and subjected to 10 x 10.5 cm SDS-PAGE (10% running gel and 4% stacking gel) with 50 µg protein loaded in each well. Molecular weight marker proteins (Bio-Rad Laboratories, Inc., Hercules, CA) were included in each experiment. After electrophoresis, proteins were transferred to polyvinylidene difluoride membranes (Bio-Rad Laboratories, Inc.), which were incubated for 1 h in 5% fat-free skim milk (Blotto/PBS) to block nonspecific binding. A Deca-probe incubation manifold (Hoeffer, San Francisco, CA) was used for primary antibody binding with patient sera diluted 1:50 in 1% Blotto/PBS and incubated overnight at 4 C on a rocker. Each blot included a positive control serum and a negative control lane with 1% Blotto/PBS only. Positive control samples included serum from a patient with lymphocytic hyphophysitis, previously shown to have strong 49-kDa pituitary autoantibody positivity (7). The membranes were then washed thrice (15 min each) with PBS-Tween 20 (0.05%), followed with PBS washes (three times, 15 min) and incubated with alkaline phosphatase-conjugated goat antihuman IgG antiserum (DAKO Corp., Glostrup, Denmark) diluted 1:2500 in 1% Blotto/PBS for 1.5 h at room temperature on a shaker. Membranes were washed again as above. Membranes were incubated with 5-bromo-4 chloro-3 indolyl phosphate and nitroblue tetrazolium until color development was optimal. Two investigators, one of whom was blinded to sample identity (P.A.C.), read the blots (Fig. 1Go). Serum TMA was assayed by hemagglutination method (Thymune-M, Murex Diagnostics, Dartford, Kent, UK) and a titer of 1:100 or more was considered positive.



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  		Figure 1. Immunoblotting of human pituitary cytosolic proteins. A, Ten percent SDS-PAGE Western blot showing specific seropositivity against 49- and 40-kDa pituitary cytosolic autoantigens by positive control serum (lane 6); negative control (1% blotto, lane 1), and healthy controls (lanes 2 and 4) with no seropositivity against 49- and 40-kDa band; patients with Sheehan’s syndrome with seropositivity against the 49-kDa autoantigen (lanes 3 and 7) and molecular weight markers (lane 5).

 
Analysis

Chi-square analysis was used to compare the frequency of pituitary antibody positivity between patient and control groups. Chi-square and t tests were used to compare the frequency and mean of different variables, respectively, in patients with Sheehan’s syndrome and "other" group as well as patients with or without PitAb positivity. A P value of less than 0.05 was considered statistically significant.

Results

Clinical details of all patients are given in Tables 1GoGo and 2Go. There was no significant difference in the mean age, duration of illness, and body mass index (BMI) between the 19 patients with Sheehan’s syndrome and the seven categorized as Other. Fourteen of 26 required hospitalization and blood transfusion immediately after delivery (10 of 19 with Sheehan’s and 4 of 7 in Other). At the time of this study, the mean postpartum duration was 6.1 ± 3.3 yr. Nine of 19 (47.3%) patients with Sheehan’s syndrome and 6 of 7 (85.7%) in Other had hypotension and/or circulatory collapse at presentation (P = 0.07). Three of them (two in Sheehan’s syndrome and one in Other) had grossly enlarged cardiac silhouettes associated with myocardial dysfunction that were successfully managed conservatively with prednisolone and T4 replacement (5). History of stillbirth or neonatal/infant mortality in the offspring during the last pregnancy was present in 10 of 19 patients (52.6%) with Sheehan’s syndrome and three of seven (42.8%) in the Other group (P = 0.65); four children were stillborn, three died on d 1, and six died between 2 and 5 months of age. Imaging revealed an empty sella (pituitary stalk descending to the floor of the cerebrospinal fluid-filled sella) in 14 (73.7%) and a partial empty sella (a thin rim of pituitary tissue along its floor) in 4 of 19 (21.0%) patients with Sheehan’s syndrome. Two subjects with partial and one subject with complete empty sella had thickened pituitary stalks. Five of seven patients in the Other group had an empty sella. Pituitary imaging was normal in one patient with Sheehan’s syndrome and in two in the Other group. Gonadotroph, corticotroph, and thyrotroph function was subnormal in all except one each in the Sheehan’s and Other groups (Table 1GoGo). None of the patients had symptoms of diabetes insipidus, either before or after hormone replacement. A bright posterior pituitary signal on magnetic resonance imaging was present in 11 of 18 patients (61.1%) with Sheehan’s syndrome and in 3 of 6 patients (50%) in the Other group.

Western blot analysis revealed PitAb positivity against the 49-kDa autoantigen in 12 of 19 (63.1%) with Sheehan’s syndrome and 1 of 7 in the Other group (Fig. 1Go). In comparison, only 4 of 28 (14.2%) controls without prior conception and 5 of 28 (17.8%) controls with prior conception had PitAb (P < 0.001 and <0.01 vs. Sheehan syndrome, respectively). Two subjects each in the Sheehan’s syndrome and controls with prior conception, but none in controls without prior conception, had autoantibodies against a 40-kDa autoantigen (P = not significant, Fisher’s exact test). When the whole cohort of 26 patients were segregated in relation to PitAb status (13 PitAb +ve and 13 PitAb -ve), no significant difference was observed in the mean age, duration of symptoms, BMI, hormone profile, imaging abnormality, and TMA positivity between the two groups. None of the nine controls with PitAb positivity had symptoms or subnormal hormone values.

Frequency and titer of TMA positivity in the Sheehan’s group (3 of 19, 15.7%) was not significantly different (Table 2Go), compared with the Other group (one of seven, 14.2%, P = 0.92), controls without prior conception (21.4%, P = 0.82), or to controls with prior conception (7.4%, P = 0.62).

Discussion

Most of the present group of patients with Sheehan’s syndrome had slow progression of their hypopituitarism with the majority presenting more than 5 yr after delivery, in a state of circulatory collapse. Other clinical features included normal BMI and very high perinatal/infant mortality in the offspring during last pregnancy (52.6%).

The pathogenesis of pituitary failure following PPH is not clear. Sheehan and Davies (6) proposed vasospasm of the pituitary vessels and consequent ischemic necrosis of the pituitary. However, experimental evidence suggests efficient adaptive autoregulation of adenohypophyseal blood flow during hypotension caused by acute blood loss (13, 14). Massive or submassive ischemic necrosis of the pituitary should result in acute pituitary failure in Sheehan’s syndrome akin to that observed in pituitary apoplexy. Maccagnan et al. (15) assessed pituitary function among patients with pituitary apoplexy managed conservatively . Two weeks following apoplexy, gonadotropin, thyrotropin, and corticotropin deficiency were observed in 80%, 50%, and 33%, respectively (15). However, in the present study, patients survived acute blood loss and related pituitary failure for several years without any hormone replacement. Despite lactational failure and amenorrhea, indicating pituitary insufficiency dating from the postpartum period, they did not seek medical attention until life-threatening symptoms of circulatory collapse because of adrenal insufficiency supervened (5, 16). This sequence of loss of pituitary trophic hormone function suggests that destruction of the pituitary gland was partial from the inception with progressive loss over time involving thyrotroph and corticotroph function. Such delayed presentation in patients with Sheehan’s syndrome could be due to the subtlety of symptomatology and thus the associated failure to recognize hypopituitarism (17). Alternatively, a mechanism, analogous to that of ischemic injury and delayed loss of gonadal function of the type seen among men with unilateral torsion of the testis, may be invoked. Many of them present later with infertility and histological abnormalities of the contralateral testis and antisperm antibodies, presumably caused by antigen release at the time of ischemic infarction (18).

There are two isolated case reports of pituitary autoimmunity in Sheehan’s syndrome (19, 20). In 1965 Engelberth and Jezkova (19), using a complement consumption test, reported PitAb in a patient with Sheehan’s syndrome. In 1982 Pouplard (20) observed PitAb by indirect immunofluorescence in three of four patients with Sheehan’s syndrome. However, in 1969 Nerup et al. (21) could not demonstrate PitAb in any of six patients with Sheehan’s syndrome. The variable reports on PitAb positivity in Sheehan’s syndrome could be due to the small numbers of patients studied or technical issues related to the immunofluorescence assays used. In the present study, 63.1% of patients with Sheehan’s syndrome had PitAb against a 49-kDa pituitary cytosolic antigen, even 5 yr after the onset of illness. However, only 14.2% of patients in the Other group had PitAb positivity. This trend of higher prevalence of pituitary autoantibody in the Sheehan’s syndrome patients with PPH suggests a relationship between the PPH and PitAb positivity. However, the difference observed in PitAb positivity between the two groups did not attain statistical significance. The comparable prevalence of TMA positivity among the study groups and controls showed no increase in the prevalence of thyroid autoimmunity in the group of Sheehan’s syndrome patients with PitAb positivity.

Recently the 49-kDa pituitary cytosolic autoantigen has been identified as the enzyme enolase (2-phospho-D-glycerate hydrolase; EC 4.2.1.11) by one of us (8, 9). The neuron-specific, {gamma}{gamma} isoform, enolase (NSE) is present in high concentration in cells of the Amine Precursor Uptake and Decarboxylation system including anterior pituitary (22, 23, 24). Its distribution correlates with the metabolic activity of the hormone-producing cells (24). Enolase catalyzes the conversion of 2 phosphoglycerate to phosphoenolpyruvate in the glycolytic pathway. It is released into serum and cerebrospinal fluid following tissue injuries including hemorrhage and shock (25).

We have demonstrated by two-dimensional gel electrophoresis and immunoblotting that sera from patients with peripartum lymphocytic hypophysitis recognize both {alpha}{alpha}-enolase (the ubiquitous form) and {gamma}{gamma}-enolase (8, 9). These isoforms share 85% homology, and it is not yet known which specific epitopes are recognized by particular patients or patient groups. We also found that NSE is expressed in the placenta and postulated that the presence of NSE in both the placenta and pituitary could explain the strong link between autoimmune pituitary disease and pregnancy (9). In the present cohort of Sheehan’s syndrome, the strongest correlation with pituitary antibodies was found in patients with significant PPH. Whether PitAb against NSE, the 49-kDa autoantigen, detected in 63.1% of patients with Sheehan’s syndrome, would bind to the active epitopes responsible for enzymatic activity of the enolase is not known. However, the occurrence of such a process after PPH and pituitary necrosis might lead to added damage and progressive hypopituitarism. Thus, to conclude, patients with Sheehan’s syndrome have serological evidence of pituitary autoimmunity even up to 8 yr after the onset of disease.

Acknowledgments

We are thankful to Dr. D. O’Dwyer for technical assistance.

Footnotes

This work was partly supported by Australian NH and MRC Grant 100952 (to P.A.C.).

Abbreviations: BMI, Body mass index; NSE, neuron specific enolase ({gamma}{gamma} isoform); PitAb, pituitary autoantibody; PPH, postpartum hemorrhage; TMA, thyroid microsomal autoantibody.

Received February 15, 2002.

Accepted June 7, 2002.

References

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