Endocrine Journal 1993, 40 (4), 431-438 A Case of Postpartum Hypopit uitarism associated with Empty Sella: Possible Relation to Postpartum Autoimmune Hypophysitis SAWA NISHIYAMA, TORU TAKANO, YOH HIDAKA, KAORU TAKADA, YosHINORI IWATANI AND NoBUYUxi AMINO Department o,f Laboratory Medicine, Osaka University Medical School, Suita 565, Japan Abstract. A fifty-year-old woman was admitted to our hospital because of generalized edema, progressive symptoms of fatigue and weakness of ten years' duration. After an uneventful third delivery, 24 years before admission, she could not lactate and developed oligomenorrhea and then amenorrhea. Laboratory evaluation revealed panhypopituitarism and pituitary cell antibodies were positive. Both CT scans and MR images showed empty sella. This case is postpartum hypopituitarism without a preceding history of excessive bleeding and may be autoimmune hypophysitis. Key words: Autoimmune hypophysitis, Postpartum hypopituitarism. (Endocrine Journal 40: 431-438, 1993) AUTOIMMUNE lymphocytic hypophysitis causes Case Report hypopituitarism during late pregnancy and the postpartum period. It was first reported in 1962 as A fifty-year-old woman, gravida 5, para 3, was a postmortem finding [1]. The first case diagnosed referred to our hospital to evaluate possible antemortem was reported in 1980 [2]. In many hypopituitarism. When she was 24 years old, at her reported cases, lymphocytic infiltration of the second delivery, she lost a considerable amount of pituitary gland caused a pituitary mass and symp- blood but she continued to have normal menstrual toms of pituitary dysfunction or chiasmal syn- periods. She uneventfully delivered her third child drome. In other mild cases, pituitary mass effects two years later. After this third delivery, she had were not seen or pituitary dysfunction became no breast engorgement nor could she lactate. Her apparent more than 20 years after delivery. It is menstrual cycle resumed, but only 4 times a year. difficult to distinguish such cases from Sheehan's She went to see a gynecologist and began taking syndrome without pituitary biopsy. There may be combination sex steroid contraceptives. After dis- many mild cases that are overseen or misdi- continuing oral contraceptives in her thirties, she agnosed. became amenorrheic and remained so. She lost We report here a patient who had gradually her pubic and axillary hair gradually, and fatigue, developed postpartum hypopituitarism and dis- weakness, facial and hand puffiness also de- cuss its possible relation to autoimmune hypophy- veloped. For several months preceding admission, sitis. she had become more drowsy and lost 4 kg in weight. She found her voice becoming hoarse. She visited a hospital and she was found to be suffering Received: January 4, 1993 from secondary hypothyroidism. She was referred Accepted: May 7, 1993 Correspondence to: Dr. Sawa NISHIYAMA, Department of to our hospital for further investigation. She had Laboratory Medicine, Osaka University Medical School, 2-2 never suffered from a severe headache accompa- Yamadaoka, Suita 565, Japan nied with visual field disturbance. 432 NISHIYAMA et al. Her height was 149 cm; weight, 48 kg; blood FITC-labeled human IgG solution was added to pressure, 118178 mmHg; and pulse rate, 64 per the cell suspension. The cells were washed again minutes. Her skin was pale and dry. She had no and fluorescence positive cells were counted axillary or pubic hair. Her face was swollen. The (PCSA). thyroid gland was not enlarged. Neurological examination was normal except for delayed re- laxation of deep tendon reflexes. Results Initial laboratory findings showed mild nor- mocytic anemia. Serum cholesterol and trig- Methods lyceride were mildly increased. Serum GOT was To evaluate the pituitary function, provocative also high but GPT and CPK were within the tests were performed during fasting with in- normal range (Table 1). travenous administration of 0.1 U of insulin per Basal serum concentrations of various hor- kilogram of body weight, 500 µg of TRH and 100 mones were as follows; ACTH: <10 pg/ml (nor- µg of LH-RH. Blood samples were drawn before mal range; <50), cortisol: 1.0 µg/dl (normal range; and 30, 60, 90, and 120 min after injection. 4.5-24), GH: <0.3 ng/ml (normal range; <5.0), Arginine (0.5 g per kilogram of body weight) was LH: 0.7 mIU/ml (normal range; 8.7-38), FSH: 4.9 given as an intravenous drip for 30 min, and mIU/ml (normal range; 26.2-113.3), PRL: 1.4 serum GH changes before and 30, 60, 90, and 120 ng/ml (normal range; <15), FT4: 0.2 ng/dl (nor- min after the beginning of the drip were evalu- mal range; 0.8-1.4), FT3: 2.1 pg/ml (normal ated. Every blood hormone was measured by range; 2.8-5.8), TSH: 4.6 µU/ml (normal range; means of a specific RIA; serum TSH was mea- 0.4-5.6). The results of detailed endocrine inves- sured by an IRMA with monoclonal antibody (SPAC-S TSH Kit, Daiichi), serum free T4 (FT4) and free T3 (FT3) by analog RIA (Free T4 Kit, Eiken, and Amerlex-M free T3, Amersham), serum GH by an IRMA (GH Kit, Daiichi), serum ACTH by IRMA (ACTH-II IRMA Kit `Mitsu- bishiyuka', Mitsubishiyuka), serum cortisol by RIA (cortisol Eiken, Eiken), serum LH and FSH by IRMA (SPAC-S LH Kit and SPAC-S FSH Kit, Daiichi), serum PRL by IRMA (SPAC-S PRL Kit, Daiichi). Anti-thyroid microsomal and anti-thyroglobulin antibodies were tested by a passive particle- agglutination method (Serodia-AMC and Serodia- ATG, Fujirebio). Anti-pituitary-antibodies (APA) reacting to rat pituitary cytoplasmic antigens (pituitary cell anti- bodies, PCA) and APA reacting to rat GH3 cells' and mouse AtT20 cells' surface antigens (pituitary cell surface antibodies, PCSA) were assayed by the method of Sugiura et al. [3, 4]. Aliquots of serum, after absorption with rat liver acetone powder, were added to rat pituitary cryostat sections and assayed by a biotin-avidin system (PCA). Heat- inactivated sera, which were also preabsorbed with rat liver acetone powder, were diluted and mixed with GH3 and AtT20 cell suspension, and kept for 30 min at 4 degrees. The cells were washed and POSTPARTUM HYPOPITUITARISM 433 tigations are shown on Figs 1-2. Serum gonado- tropin (LH and FSH) did not respond to LH-RH (Fig. 1A). Serum PRL did not increase after TRH administration, but TSH showed a blunted re- sponse (Fig. 1B). An insulin tolerance test showed no response of ACTH, GH or cortisol (Fig. 2A). The serum GH level did not change at all after arginine infusion (Fig. 2B). Anti-pituitary-antibodies (APA) reacting to rat pituitary cytoplasmic antigens (pituitary cell anti- bodies) were positive, but APA reacting to rat GH3 cells' and mouse AtT2o cells' surface antigens (pituitary cell surface antibodies) were negative. She had neither anti-thyroid microsomal nor anti-thyroglobulin antibodies. Antinuclear anti- bodies were negative, either. Both magnetic resonance (MR) images (Fig. 3A), and computed tomography (CT) scans (Fig. 3B) showed empty sella. The patient was diagnosed as having panhypo- Fig. 2. A: GH, cortisol, and ACTH responses to insulin tolerance test. Hypoglycemia was induced with 0.05 U/kg regular insulin given as an intravenous bolus. B: GH response to arginine. Arginine (0.5 g/kg) was given as an intravenous drip for 30 min. pituitarism. She responded well to thyroid replace- ment and hydrocortisone with resolution of her symptoms. Discussion We treated a patient with postpartum hypopi- tuitarism that developed after her third, unevent- ful delivery. There are three main causes of postpartum hypopituitarism: Pituitary adenoma, Sheehan's syndrome and autoimmune lymphocy- tic hypophysitis. Pituitary microadenoma did not agree with her clinical course, and neither CT scans nor MR images showed pituitary adenoma but empty sella. Although Sheehan's syndrome is so common that many cases with postpartum hypopituitarism are diagnosed as that syndrome, it is difficult to suppose that she suffered from Sheehan's syndrome. She had abnormal bleeding at her second delivery, but she resumed normal Fig. 1. A: LH and FSH responses to LH-RH. B: Prolactin and TSH responses to TRH. LH-RH (100µg) and menstrual cycles and became pregnant with her TRH (500 µg) were given together as an in- third baby. travenous bolus. Recently autoimmune lymphocytic hypophysitis 434 NISHIYAMA et al. has been recognized as a cause of hypopituitarism tis frequently causes ACTH and TSH deficiency. during late pregnancy and the postpartum period. There was sometimes hyperprolactinemia hap- Patients who had symptoms indicating a pituitary pened with a pituitary mass that probably com- mass were operated on and the diagnosis was pressed the adjacent stalk and interfered with the histologically confirmed. On the other hand, there delivery of prolactin-inhibiting factors. was no clinical indication to have a pituitary biopsy It is difficult to know whether or not the patients for patients with pituitary hypofunction without who had pituitary hormone deficiency had reco- pituitary mass effects. Such cases were thought to vered normal pituitary function without biopsy, be "possible autoimmune hypophysitis" with co- because most patients were operated on as soon as existent autoimmune diseases or auto-antibodies. the masses were found. Some patients who had According to her history and the presence of "possible" lymphocytic hypophysitis-hypopi- anti-pituitary-antibodies, she probably had auto- tuitarism and (or) pituitary masses which were not immune lymphocytic hypophysitis which occurred surgically treated-recovered [43, 46], but others after her third delivery. It is difficult to recognize did not [40-42, 44, 45]. such a mild case soon after the onset of the disease, Out of 17 pregnant patients, 14 showed signs of because the symptoms of hypopituitarism are not hemianopia and 6 patients' vision grew worse after distinctive-for example, fatigability, amenorrhea, delivery.