Triphasic changes in thyroid function in a patient with primary hypothyroidism in the course of pregnancy and the early post-partum period.

We report a rare case of primary hypothyroidism in which thyroid function was changed from hypothyroidism to hyperthyroidism in the course of pregnancy and finally returned to hypothyroidism in the early post-partum period. She delivered an infant with neonatal Graves' thyrotoxicosis. Serum thyroid-stimulating antibodies (TSAb) and thyroid stimulating-blocking antibodies (TSBAb) coexisted in these patients. The triphasic changes in thyroid function may be explained by altered balance between TSAb and TSBAb in relation to pregnancy and delivery in the present case, although cellular immunity could be independently involved in atrophic changes in the postpartum period.

Clinical courses and thyroid conditions in three infants born to a mother with thyroid stimulating-blocking antibodies.

The clinical courses including thyroid conditions of three infants born to a mother with primary hypothyroidism due to Hashimoto's thyroiditis were studied. The mother was positive for both TSH-binding inhibitor immunoglobulins (TBII) and thyroid stimulating-blocking antibodies (TSBAb) in her serum. The first infant died because of septic shock due to fistula formation between the large intestine and the bladder. Serum thyroid hormone levels during the first pregnancy were extremely low because of incomplete replacement therapy with levothyroxine. The second infant had almost normal thyroid function, so that the replacement therapy was not necessary. The third infant had transient and overt primary hypothyroidism. The replacement therapy was carried out for six months after birth. TSBAb activities in this mother were high in the third pregnancy. In general, these activities gradually increases with the clinical course in TSBAb-positive Hashimoto's patients. From these findings, it was suspected that the thyroid conditions in the second and the third infants reflected the natural course of TSBAb activities in this mother.

Incidence of hyperprolactinemia in patients with Hashimoto's thyroiditis.

The causes of hyperprolactinemia, the correlation between serum levels of PRL and thyroid function and magnetic resonance imaging (MRI) of the pituitary were studied in patients with chronic thyroiditis. Seventy-four female patients and 15 normal control women participated in this clinical survey. Fourteen of 74 patients with various thyroid conditions had increased serum PRL. The incidence of hyperprolactinemia in the overt primary hypothyroid group was 42.4% and was significantly higher than in any other group with normal serum thyroxine. There was a close association between the increment in serum PRL and of free triiodothyronine above the basal level after TRH administration. There were 14 patients with hyperprolactinemia in three of which serum PRL was over 60 micrograms/L. PRL producing tumor, severe primary hypothyroidism and liver cirrhosis were detected in these three patients, respectively. These results indicate that the pathogenesis of increased serum PRL was not uniform in patients with Hashimoto's thyroiditis, although there was a correlation between hyperprolactinemia and impaired thyroid function. It is proposed, therefore, to measure and follow serum levels of PRL and MRI of the pituitary in patients with chronic thyroiditis, especially with impaired thyroid function.

Unique case of growth hormone (GH) deficiency accompanied by clinical anophthalmia, hypoplastic orbits, digital dysplasia, short stature, obesity, and diabetes mellitus.

A 43-year-old female was admitted to our hospital for polydipsia and hyperglycemia. She had total blindness and globes were not recognized by inspection, indicating clinical anophthalmia. Physical examination revealed short stature, obesity, prematurely gray hair, shortness of fingers and toes, syndactyly, and multiple dental caries. Laboratory examination showed hyperglycemia, increased glycosilated hemoglobin (HbA1c) and insulin resistance on euglycemic glucose clamp. Blunted growth hormone (GH) secretion was shown in response to insulin-induced hypoglycemia, arginine infusion, and GH-releasing hormone (GHRH) loading test, and in 24 h spontaneous GH profile. Magnetic resonance imaging (MRI) and computed tomography (CT) showed dysostosis of orbit, defect of optic nerve, enlarged suprasellar cistern, and prolonged pituitary stalk. This may be the first report of a unique case with GH deficiency accompanied by clinical anophthalmia, hypoplastic orbits, digital dysplasia, short stature, obesity, and diabetes mellitus.

[Treatment with bolus methylprednisolone for pure red cell aplasia after ABO incompatible bone marrow transplantation in a patient with chronic myelocytic leukemia].

Pure red cell aplasia (PRCA) was found in a male patient with chronic myelocytic leukemia after major ABO incompatible bone marrow transplantation (BMT). He had blood group O, and received BMT from an HLA identical sibling (blood group A). Erythrocyte-depleted marrow was transplanted. Methotrexate for short time and cyclosporine (CyA) were used for graft versus host disease (GVHD) prophylaxis. Engraftment of neutrophils and platelets were observed on day 14 and 22, respectively. The Ph1 chromosome disappeared on day 133. However engraftment of erythrocytes was not observed on day + 280. Bone marrow puncture revealed depletion of erythrocyte precursors. Anti-A isoagglutinin was persisted. There was no evidence of acute or chronic GVHD. Administration of prednisolone, discontinuance of CyA and subcutaneous infusion of recombinant human erythropoietin failed to improve PRCA. Bolus methylprednisolone (m-PSL) therapy started on day 284 resulted in rapid increase in reticulocyte counts within 6 days, which was followed by normal hemoglobin concentrations. We conclude that bolus m-PSL may be one treatment for PRCA after BMT.

Correlation of plasma free thyroxine levels with insulin sensitivity and metabolic clearance rate of insulin in patients with hyperthyroid Graves' disease.

Insulin sensitivity, metabolic clearance rate of insulin (MCR-I) and basal posthepatic insulin delivery rate (BIDR) were investigated by means of euglycemic clamp technique in 8 normal subjects and 8 patients with hyperthyroid Graves' disease. The mean (+/- SD) steady-state glucose infusion rate (SSGIR) was lower in hyperthyroid Graves' patients than in normal subjects (228.9 +/- 57.0 vs. 290.9 +/- 49.4 mg/m2/min, p < 0.05). Both MCR-I and BIDR were higher in hyperthyroid Graves' patients than in normal subjects (1162.9 +/- 517.1 vs. 463.5 +/- 103.9 ml/m2/min, p < 0.005; 17.7 +/- 12.6 vs. 3.6 +/- 0.9 mU/m2/min, p < 0.01, respectively). Plasma free T4 levels showed a close correlation with MCR-I (r = 0.77, p < 0.05) and BIDR (r = 0.81, p < 0.05), respectively, in Graves' patients. These findings indicate that hyperthyroidism is characterized by not only a decrease in insulin sensitivity, but also an increase in basal insulin secretion and the metabolic clearance rate of insulin, which are correlated with plasma free T4 levels.

Effect of continuous subcutaneous administration of a small dose of granulocyte colony stimulating factor (G-CSF) by the use of a portable infusion pump in patients with non-Hodgkin's lymphoma receiving chemotherapy.

The effects of continuous subcutaneous infusion (CSI) of human granulocyte-colony stimulating factor (G-CSF) on the absolute neutrophil count (ANC) and serum G-CSF level were examined in 11 patients with non-Hodgkin's lymphoma (NHL) during cytotoxic chemotherapy. Recombinant G-CSF (rG-CSF) was subcutaneously infused using a portable infusion pump at a constant flow rate of 1 microgram/20 microliters/h for 14 days starting 2 days after the end of the second course of chemotherapy. The ANC was lowered after the chemotherapy without rG-CSF infusion whereas the duration of neutropenia and the nadir level of the ANC after the chemotherapy were ameliorated by the combined administration of rG-CSF (mean +/- S.E., 0.6 +/- 0.5 days vs. 4.7 +/- 1.9 days, P < 0.05; 455 +/- 135/microliter vs. 1906 +/- 598/microliter, P < 0.05). Serum G-CSF levels increased after the start of rG-CSF infusion, reaching a mean peak value of 418.5 +/- 128.5 pg/ml at the 8th day, and then returned to the basal level (35.6 +/- 13.5 pg/ml) immediately after the end of continuous infusion of rG-CSF. Although a slight increase in serum G-CSF was obtained in the patients after the chemotherapy without rG-CSF administration, the mean serum level was much lower than that in the patients after the chemotherapy with rG-CSF administration (88.2 +/- 24.8 pg/ml vs. 199.6 +/- 20.6 pg/ml, P < 0.01). No notable side effects of the CSI of rG-CSF were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effective treatment with constant subcutaneous infusion of octreotide in a patient with acromegaly associated with diabetic pre-coma and diabetes insipidus].

A 58-year-old woman was admitted to our hospital for impaired consciousness, hyperglycemia and bitemporal hemianopsia. She was diagnosed as having NIDDM one year ago and was treated with diet and glibenclamide (1.25 mg/day) for 6 months. However, she stopped her medical treatment one month ago and then polydipsia and general fatigue were manifested. She was admitted to a hospital five days ago at which time hyperglycemia (405 mg/dl) and anemia (Hb8.0g/dl) were detected. She was transferred to our hospital for control of blood glucose and further examination of bitemporal hemianopsia. She showed typical acromegalic features including enlargement of the nose, lips and tongue, increased heel pad and acral growth. Conscious disturbance was cured by the infusion of saline and the administration of insulin. Endoscopy revealed an active gastric ulcer (A1). Endocrine data disclosed increased GH levels in plasma and urine, whereas plasma IGF-1 levels were low. Plasma GH paradoxically increased following the administration of TRH. A water deprivation test showed an impaired increase in urinary osmolarity, indicating partial central diabetes insipidus (DI). MRI with Gd-contrast revealed a macroadenoma which progressed toward suprasella. She was diagnosed as having acromegaly, partial DI and probable hyperosmolar hyperglycemic nonketotic diabetic pre-coma. Polyuria (5-101/day) due to partial DI was controlled by the administration of DDAVP (10 micrograms/day). The constant subcutaneous administration of octreotide (240 micrograms/day) resulted in normal plasma GH levels and a marked shrinkage of the pituitary tumor. The pituitary tumor was finally removed by the transsphenoidal approach following treatment with octreotide for 4 months. HE staining of the pituitary tumor showed atrophic and acidophilic cells surrounded by hyaloid connective tissue. After the surgery, plasma GH levels were normalized and complications were cured. In conclusion, this is a very rare case of acromegaly associated with diabetic pre-coma and partial DI, and effectively treated with constant subcutaneous infusion of octreotide.

[Effect of arotinolol on insulin secretion and insulin clearance rate in patients with Graves' disease].

Glucose-induced insulin secretion, 24-h urinary C-peptide (CPR) and euglycemic clamp were examined in five patients with hyperthyroid Graves' disease before and 2 weeks after treatment with arotinolol (20 mg/day, p.o.). Plasma glucose and insulin responses to oral administration of 75 g glucose were not changed by arotinolol treatment. 24-h urinary CPR and basal posthepatic insulin delivery rate (BPIDR) as an indicator of insulin secretion were significantly suppressed by arotinolol. Glucose infusion rate (GIR) as an indicator of insulin sensitivity and glucose clearance rate (GCR) were not influenced by arotinolol therapy. Insulin clearance rate (ICR) was significantly suppressed by arotinolol. These findings suggest that arotinolol inhibits insulin secretion by decreasing ICR but does not attenuate insulin release induced by glucose in hyperthyroid patients, and that insulin sensitivity and GCR are not affected by arotinolol.

[A case of Cushing's disease associated with a non-functioning adrenal tumor].

A 52-year-old woman was admitted to our hospital for further examination of central obesity, hypertension and hirsutism suggesting Cushing's syndrome. Hirsutism had been remarkable for two years, and muscle weakness of the lower extremities gradually developed during the past year. CT scan revealed a tumor in the left adrenal gland which was 1 cm in diameter, round, well-circumscribed, homogeneous and not enhanced. Endocrine data disclosed increased urinary 17-OHCS (11.5-16.4 mg/day) and elevated plasma ACTH (125 pg/ml) and cortisol (19 micrograms/dl) with a lack of diurnal rhythm. Administration of the single-dose dexamethasone (1mg) did not suppress plasma cortisol. However, consecutive administration of either 2mg or 8mg of dexamethasone for 2 days suppressed both plasma cortisol and urinary 17-OHCS. Administration of metyrapone raised both urinary 17-OHCS and plasma ACTH levels. Rapid ACTH test resulted in a hyperresponse of plasma cortisol. CRF injection raised plasma ACTH and cortisol. Bilateral adrenal glands were well demonstrated by 19-iodocholesterol (I-131) scintigraphy during the administration of dexamethasone. MRI with Gd-contrast revealed a microadenoma in the sella turcica. With the diagnosis of Cushing's disease, the microadenoma was removed by the transsphenoidal approach and adrenal function was normalized. However, the left adrenal tumor remained on CT scan but was not demonstrated by scintigraphy. These findings indicate that this is a very rare case of Cushing's disease which was associated with an unilateral non-functioning adrenal tumor.

[Effect of subcutaneous administration of interleukin-1 beta on blood platelet count and serum GM-CSF in patients with myelodysplastic syndrome and aplastic anemia].

Subcutaneous administration of recombinant human Interleukin-1 beta (IL-1 beta) in a dose of 1-3 x 10(4) U/day for 14 to 72 days resulted in an increase in circulating granulocytes and bone marrow monocytes in all the 4 patients examined. Circulating platelet count was also increased in two of four patients with myelodysplastic syndrome (MDS) and aplastic anemia (AA). Bone marrow examination revealed an increase in megakaryocyte count in these patients, whereas the percentage of blast was not changed. An increase in blood platelet count was accompanied by an increase in serum GM-CSF in a patient with AA, whereas serum IL-6 level was not changed throughout the treatment with IL-1 beta. These findings suggest that IL-1 beta may be useful for the treatment of a proportion of patients with MDS and AA who are associated with thrombocytopenia.

[Clinical use of serum erythropoietin determination by the recombigen EPO RIA kit].

Serum erythropoietin (EPO) levels were determined by the recombigen EPO RIA kit (DPC) in normal subjects and patients with renal dysfunction, diabetes mellitus, hypothyroidism and a variety of hematological disorders. Mean (+/- SD) serum EPO levels were 18.6 +/- 5.6 mU/ml in 180 normal subjects and no sex difference was obtained. Serum EPO levels in older subjects were slightly greater than those in younger subjects. There was a negative correlation between serum EPO levels and Ht values in anemic patients with normal renal function, whereas serum EPO levels were within the normal range in anemic patients with renal disorders, suggesting that serum EPO levels were relatively low in patients with chronic renal failure. Serum EPO levels were rather increased in patients with diabetes mellitus and hypothyroidism. High serum EPO levels were obtained in patients with a variety of hematological disorders such as acute leukemia, multiple myeloma, myelodysplasia syndrome, aplastic anemia and pure red cell aplasia. In a patient with pure red cell aplasia treated with glucocorticoids, serum EPO levels were lowered before anemia was recovered and reticulocytes were increased. These findings indicate that measurement of serum EPO levels are useful for not only differential diagnosis of anemia but also clinical evaluation of the treatment.

[A case of type 1 diabetes mellitus with hypothalamic amenorrhea: successful pregnancy following subcutaneous pulsatile administration of LHRH].

A 27-year-old woman with type 1 diabetes mellitus was admitted to the Shimane Medical University Hospital because of secondary amenorrhea. She had been treated with insulin since July, 1986. Fasting plasma glucose and HbA1c levels were controlled within normal limits. However, body weight gradually decreased and amenorrhea started in 1988. Physical examination revealed emaciation with BMI of 17.3. Basal levels of plasma T3, somatomedin C, LH, FSH and estradiol levels were low, whereas HGH levels were slightly elevated. Plasma LH markedly increased in response to LHRH administration. She was diagnosed as having weight loss-related hypothalamic amenorrhea. Induction of ovulation was not obtained with clomiphene citrate. Treatment with subcutaneous pulsatile administration of LHRH (20 micrograms every 120 min) resulted in an increase in plasma levels of LH, FSH and estradiol, which was accompanied by ovulation and corpus luteum formation. Further treatment with pulsatile LHRH administration was followed by conception. Two gestational sacs were detected by ultrasonography. One of them was absorbed at the early stage of pregnancy. She was delivered of one healthy female infant without complications. These findings suggest that it is important not only to control plasma glucose levels but to keep the appropriate weight and support the psychological aspects of the subject in the treatment of diabetes mellitus. Subcutaneous pulsatile LHRH therapy may be effective for the induction of ovulation in clomiphene-resistant hypothalamic amenorrhea; however, it will be necessary to solve the problem of dosage and the interval of LHRH administration in the future.

[A case of adult T-cell leukemia (ATL) complicated with multiple nocardial abscesses].

A 45-year-old woman was admitted to our hospital with complaints of fever and lumbago. She was treated for adult T-cell leukemia and thrombocytopenia with 20 mg/day of prednisolone. CT scan showed multiple abscesses in right peri-kidney, right iliopsoas muscle, left subcutaneous region in the abdominal wall and the brain. Left subcutaneous abscess was drained. Gram-positive organisms consisting of filaments were found, and Nocardia farcinica was grown in cultures. After two months of chemotherapy (FMOX, MINO and AMK), all abscesses except one in the brain disappeared. Cerebral abscess was cured fifty days after the start of the treatment with oral administration of Sulfamethoxazole-trimethoprim (SMX/TMP). The mortality of Nocardial cerebral abscess is high. This patient is a very rare case in which multiple Nocardial abscesses including brain abscess was cured by chemotherapy.

Insulin release from the pancreas and fuel metabolism during late gestation in chemically diabetic rats.

The effects of chemical diabetes and fasting on fuel metabolism and insulin secretory activity in late pregnancy were investigated. Female Wistar rats were made chemically diabetic (CD) by intravenous injection of streptozotocine (30 mg/kg) 2 weeks before conception. When CD pregnant rats were fed, plasma glucose and insulin levels were not significantly different from those of normal pregnant rats. Ketone body levels, however, were higher in CD pregnant rats than in normal pregnant rats, indicating insulin resistance in CD rats. Insulin secretion from the perfused pancreas caused by arginine or glucose was markedly decreased in CD pregnant rats. The pregnant rats were fasted for 2 days, from day 19 to 21 of gestation. Plasma glucose and insulin concentrations decreased similarly in the two groups, whereas ketone body concentrations in CD pregnant rats were significantly higher than those in normal pregnant rats. Glucose-induced insulin secretion by the perfused pancreas was markedly attenuated by fasting and was not significantly different in normal and CD pregnant rats. These observations suggest that diabetes mellitus accelerates starvation in late gestation, due to increased insulin resistance and poor insulin secretion, and that fasting in diabetic pregnancy amplifies ketogenesis.

Effect of starvation on nutrition and insulin secretion in pregnant rats and their fetuses.

Pregnancy is thought to create a metabolic condition of accelerated starvation. To clarify this idea, the effect of fasting on pregnant rats (day 21 of gestation) and their fetuses was examined. Although pregnancy significantly increased plasma insulin, plasma ketone body concentrations in fed pregnant rats were higher than those of age-matched fed virgin rats. After 48 hr fasting (i.e., fasting during days 19-21 of gestation), plasma insulin was markedly decreased in virgin rats compared with term pregnant rats, while ketone bodies were significantly higher in pregnant rats than in virgin rats. Body weight was lower in fetuses from fasted mothers than those from fed mothers. Starvation also markedly diminished the insulin response to glucose in isolated, perfused pancreases in both virgin and pregnant rats. The amount of insulin released during glucose stimulation was greater in pregnancy, and the inhibitory effect of 48 hr fasting on insulin release was greater in virgin rats than in pregnant rats. It is possible, therefore, that in term pregnant rats a decrease in insulin release caused by fasting may cause more profound catabolism than in nongravid rats.

Rat fetal islets as a useful model for the study of insulin release failure.

To study the mechanism of imparied insulin secretion from rat fetal islets, the insulin responsiveness of islets from fetuses (day 21.5 of gestation) to a variety of secretagogues was compared with that of adult rat islets. Forskolin (30 microM)-induced insulin release from fetal and adult islets was 2.7-and 2.5-fold higher, respectively, than that from islets treated with 5.6 mM glucose alone. The effects of 12-O-tetradecanoyl phorbol-13-acetate (TPA) (200 nM) were also similar in fetal and adult islets. Thus, the responsiveness to forskolin and TPA showed no significant difference in adult and fetal islets. A synergistic effect of combinations of various insulin secretagogues was observed in adult islets; however, a weak synergistic effect was present with gliclazide plus TPA only in fetal islets. After islets were cultured in RPMI 1640 (containing 11.1 mM glucose), gliclazide-, forskolin-, and TPA-induced insulin release reached the levels obtained in adult islets. However, the synergistic effect of gliclazide and TPA disappeared after culture of the islets. These results suggest that the poor insulin secretion from fetal islets is not due to a defect in the activating system of either cAMP or C-kinase, but to the immaturity of the interaction of those messenger systems.