We review the 35 cases with pheochromocytoma associated with pregnancy including our own 3 cases in the Japanese literature from 1958 to 1993. In a total of 35 cases, the overall maternal mortality rate was 11% and the fetal loss 22%. Recently, after 1981, the maternal mortality rate and the fetal loss were significantly reduced to one patient (6%). Although antepartum diagnosis of pheochromocytoma was made in only 32% of the patients, maternal mortality was reduced to zero and fetal loss to 18%. An initial diagnosis of toxemia of pregnancy was made in 17 patients (49%) and of pheochromocytoma in 10 patients (29%). A diagnosis of pheochromocytoma was made before delivery in 11 patients (31%), after delivery in 22 patients (63%), at autopsy in one patient (3%), and unknown in one patient (3%). The symptoms mostly suggestive of pheochromocytoma were paroxysmal hypertension in 27 (77%) of the 35 patients. The clinical symptoms generally appeared in the third trimester in 23 patients (66%). Pheochromocytoma is a rare disease, but a high index of clinical suspicion must be kept in mind and pheochromocytoma must be listed in the differential diagnosis of hypertension associated with pregnancy. Recently, abdominal ultrasound study and MR imaging can be used to localize the tumor during the antepartum period. Once the diagnosis is confirmed, alpha-blockade is essential and beta-blockade may be required. In the first and second trimesters, tumor resection has a good fetal outcome; in later pregnancy, delivery by elective caesarean section followed by tumor resection is recommended.

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Although fine needle aspiration biopsy (FNAB) is most valuable in the diagnosis of thyroid cancer, it is hampered by the fact that no specimen suitable for cytological examination can be collected from all cystic lesions. Often inadequate aspirates, consisting only of fluid or a few foamy cells and lacking the necessary epithelial cells, are all that an aspirationist is able to collect. Therefore an alternative method of determining the benign or malignant characteristics of cyst fluid is of vital importance. In this study we examine thyroglobulin (Tg) concentrations and lactic dehydrogenase (LDH) isozyme patterns of cyst fluid and discuss how these variables help us estimate the probability of malignancy. Fiftythree differentiated cancers (39 papillary and 14 follicular carcinomas) and 72 surgically resected benign thyroid nodules (40 adenomas, 19 colloid goiters, and 13 cysts) were analyzed. Only 28 (53%) of 53 malignant lesions were correctly diagnosed by FNAB. The mean logarithmic value for the Tg concentration (log₁₀ Tg) was significantly lower in malignant cyst fluid than it was in benign nodules (mean±SD: 5.8±1.0 vs. 6.8±1.0; P<0.001). The LDH 1 and 2 isozyme percentage was greater in the malignant group than in the benign group (49.1±12.7% vs. 38.1±16.9%; P<0.01). In multiple logistic regression analysis, log₁₀ Tg and the total of LDH 1+2 percentage was significant in estimating the probability of malignant nodules. The results of our study suggest that determining the Tg concentration and the LDH isozyme patterns of cyst fluid could provide new information for the evaluation of cystic thyroid nodules.

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Cysteamine, a specific somatostatin depleter, was given to male rats to clarify its role in relation to the renin-angiotensin-aldosterone (RAA) axis and glomerulosa cell growth. Rats received seven daily sc injections of cysteamine at doses of 50 or 150mg/kg body weight (BW). Their adrenal weights and whole cortical thickness increased, but zona glomerulosa thickness decreased dose-responsively. Plasma renin activity (PRA) and aldosterone concentration (PAC) decreased. Similar results were observed in rats on a low or high salt diet and receiving daily doses of 150mg/kg BW of cysteamine. In hypophysectomized rats, however, cysteamine given for seven days at daily doses of 100mg/kg BW did not change either PRA or PAC. Adrenal weight did not change either too. Our results indicate that cysteamine suppresses the RAA axis and glomerulosa cell growth, probably through pituitary factors.

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A retrospective study was performed to determine the reliability of physical examination (PE), ultrasonography (US) and fine-needle aspiration cytology (FNA) in the evaluation of thyroid nodules. Preoperative diagnoses of 252 euthyroid patients comprised 126 with benign lesions, 114 with papillary carcinoma and 12 with follicular carcinoma made by PE, US and FNA were reviewed. The specificity of PE, US and FNA for malignancy was 98%, 90% and 98%, respectively. The sensitivity of PE, US and FNA for malignancy was 63%, 78% and 80%. The sensitivity for papillary carcinoma of the three procedures was 68%, 83%, 88%, whereas that for follicular carcinoma was 25%, 25%, 8%, respectively. When all the test results were negative, the likelihood ratio favoring papillary carcinoma was 0.008 whereas that favoring follicular carcinoma was 0.6. The histological category of carcinoma should be considered when evaluating diagnostic procedures for thyroid nodules. No negative test result is conclusive for ruling out the possibility of follicular carcinoma.

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Mammary cells were prepared from lactating mice by collagenase digestion in order to examine the reaction of prolactin (PRL) with its cellular receptors. Cells were treated with 10% acetic acid following PRL binding. Between 5 and 12.5% acetic acid, the dissociation of PRL remained constant. The ratio of dissociated PRL was comparable to that of tissue slices or disrupted cells with this treatment. In subcellular membranes, about 81% of PRL bound to plasma membrane receptors was dissociated by acid treatment while PRL dissociated from intracellular membrane receptors was about 21%. Based on the nature of their PRL dissociation, PRL receptors were classified as acid-sensitive or acidinsensitive. The reaction of PRL with either species was reversible and saturable, and was dependent on temperature and time. Both species showed high PRL-binding affinity. However, acid-insensitive receptor was unstable at 37°C. The level of acid-sensitive receptor was close to that of acid-insensitive receptor in late pregnancy. During the first 3 days of lactation, the level of acid-sensitive receptor increased more slowly than that corresponding to acid-insensitive receptor. The above criteria suggest that the postpartum increase in PRL binding is characterized especially by an increase in the level of acid-insensitive PRL receptor located mainly on intracellular membrane.

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Quantitative analysis of the positive and negative feedback actions of testosterone (T) was carried out using intact rats, and orchidectomized rats implanted with T-filled Silastic capsules. Target organ weights and serum levels of LH and T were examined 7 days later, and response ratios of positive and negative actions were plotted against logarithm of serum T. From x-intercepts and slopes of regression lines, thresholds and responsiveness of reactions were calculated, respectively. Maintenance T levels necessary to maintain onset weights of the organ were also calculated from the regression lines. We compared 5 parameters at various ages, 1) thresholds for lowering serum LH, 2) mean T concentration of intact animals, 3) upper limit of serum T (mean + 2SD), 4) maintenance T levels, and 5) lower 95% limit of the thresholds for target organ response in orchidectomized animals. Though T can act between thresholds for target organ response and upper limit of serum T, the action range of T to induce organ growth over the onset organ weight (growth-inducing range) should be the area between the maintenance T level and the upper limit for serum T. At 3 weeks of age, the threshold for serum LH was very low, which makes the upper limit of serum T lower than maintenance T, allowing no growth-inducing range. From 5 weeks of age, the threshold for serum LH increased, and the serum T level with its upper limit also increased over the maintenance T level, allowing the presence of a growth-inducing range of T to make the growth of target organs possible.

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The recent increasing use of ultrasound and computed tomography has revealed numbers of incidentally discovered adrenal tumors. Many studies have focused on their surgical management, but the biological characteristics of these adrenal tumors have remained unclear. Adrenal tumors were resected from 10 patients who underwent gastrectomy or cholecystectomy. No signs or symptoms of adrenal hormone excess or deficiency were evident either before or after the operation. Moreover, after surgery, no major differences in signs and symptoms including blood pressure levels were observed. Before surgery, neurogenic tumors and cysts were excluded by enhanced magnetic resonance imaging. Steroid contents and both the activities and amounts of steroidogenic cytochrome P-450s in the adrenocortical adenomas of these patients were examined. Microscopic examination revealed that the tumors were surrounded by a thin, non-intact capsule; the surrounding cortex was not atrophic and apparently normal; and the cells of both the tumor and adjacent portions were arranged in nests and cords. Measurements of all steroid content (pregnenolone, progesterone, corticosterone, 11-deoxycorticosterone, 18-hydroxydeoxycorticosterone, cortisol, and dehydroepiandrosterone) except aldosterone in 5 resected adrenal tumors were within the normal ranges for the adrenals of 5 patients with renal cell carcinoma. Aldosterone content in tumor portions was significantly lower than in the apparently normal adrenals. Although in both tumor and adjacent portions of another 5 resected adrenal tumors the activities and amounts of cytochrome P-450s (P-450_scc', P-450_11β', P-450_aldo', P-450_17α', and P-450_c21) were also within the normal ranges, the activities of P-450_scc and P-450_17a in the tumor portion were greater than those in the adjacent portion. Grossly well-demarcated yellowish-brown tumors of the adrenal gland were observed in all the cases of adrenal tumor. The above results suggested that adrenal incidentalomas produce adrenal steroids through steroidogenic enzymes in both the tumor and adjacent portions. In addition, decreases in aldosterone content and increases in the activities of P-450_17α in tumor portions suggest the shift of steroidogenesis from a mineralocorticoid pathway to a glucocorticoid pathway.

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A 68-year-old man was hospitalized in August, 1990 with general malaise, loss of energy, poor appetite and severe depression. He had experienced depressed moods, markedly diminished interest, feelings of worthlessness, diminished ability to think, general malaise and muscle weakness beginning in November, 1989. He was treated for depression at another hospital until his emergent admission to our hospital because of difficulty in walking. Laboratory studies disclosed hyponatremia, low plasma ACTH level (4.2pmol/L), and a low cortisol level (27.6nmol/L). Rapid ACTH test elicited an increase in serum cortisol from 75.6nmol/L to 361.2nmol/L at 30min. Ovine corticotropin releasing hormone (CRH) did not stimulate secretion of either ACTH or cortisol. Human growth hormone releasing hormone (GRH) together with thyrotropin releasing hormone (TRH) elicited a normal response of TSH and low responses of GH and PRL. The patient's serum autoantibodies to anterior pituitary cell membranes using GH3 rat pituitary cells and AtT-20 mouse pituitary cells were positive. On the basis of these data, the diagnosis of selective ACTH, GH and PRL deficiency was made and thought to have been caused by lymphocytic adenohypophysitis. Following cortisol replacement therapy, he quickly regained his appetite and was restored to a normal mental state of being.

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A patient with an apparently normal 46, XY karyotype, suffering from pure gonadal dysgenesis and of short stature was investigated. The patient, who was growth retarded, was a 30-year-old married Japanese woman with a history of primary amenorrhea and infertility with a weight of 42 kg and a height of 146cm. She has a phenotypically and karyotypically normal dizygotic twin brother with normal development. Southern-blot and polymerase chain-reaction analyses revealed no apparent deletions in the patient's Y chromosome, including the sex-determining region Y (SRY). The DNA sequencing of the SRY gene showed a 100% nucleotide sequence identity with the reported cloned sequence. Sex reversal in the present case may be due to mutation at a locus other than SRY in the sex determining pathway, a gene potentially involved in the determination of human constitution.

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Intracranial germ cell tumors are known to be frequently associated with anterior pituitary hypofunction and diabetes insipidus. In general, these manifestations are not ameliorated even after successful radiotherapy. Since platinum based chemotherapy is introduced as a therapeutic approach to these tumors, its effectiveness is compared with the outcome obtained by radiotherapy in terms of tumor regression and endocrine functions. In this study, six patients received conventional radiotherapy and one received chemotherapy as an initial treatment. In all patients, complete remission was achieved irrespective of the therapeutic method. Their diabetes insipidus was not improved. Many patients treated with radiotherapy did not show the complete improvement of pre-existing hypofunction of the anterior pituitaries. In contrast, chemotherapy achieved almost complete hormonal remission. These clinical observations suggest that chemotherapy is quite effective in oncological as well as endocrino-logical aspects in treating intracranial germ cell tumors.

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We examined the effects of insulin on bone formation including the mineralizing process. Twenty-day fetal rat parietal bones were cultured for 96h on grids in a serum-free medium. For the precise assessment of bone formation, histomorphometry, with an image analyzing system, was used to measure the areas of mineralized bone and bone matrix, and the numbers of osteoblasts and osteoclasts. In order to confirm the effects of insulin on bone mineralization, the calcium content of the bone and the release of previously incorporated ⁴⁵Ca into the medium were measured. Insulin, at a concentration of 10^-6M or higher, increased the areas of mineralized bone and bone matrix, and the number of osteoblasts. Osteoclasts were seldom observed in bones on day 0 or in bones treated with insulin. In bones treated with insulin at a concentration of 10^-6M, the calcium content of bone increased. At an insulin concentration of 10^-7M or higher, the dry weight of decalcified bone increased. Lactate production in the medium increased dose-dependently. The inhibited release of ⁴⁵Ca in bones indicated that insulin acts by increasing calcium retention. We demonstrated that insulin has an effect on bone-forming and bone-resorbing cells to enhance the bone forming process from matrix formation to mineralization.

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We analyzed point mutations of N-ras protooncogene codon 61 in thyroid neoplasms by means of a mutation-specific PCR method. In this method, one of the paired primers has a base at the 3' terminal that is complementary to a mutated base of the DNA sequence to be analyzed. With this primer, only alleles which have the same mutation can be amplified. Among 24 thyroid tissues, we detected 2 point mutations out of 7 follicular carcinomas (29%). One tumor had a cytosine to adenine substitution mutation at the first base of codon 61, and the other had an adenine to guanine substitution mutation in the second base of the same codon. The same mutations were not detected in 7 follicular adenomas or 1 papillary carcinoma. These results were confirmed by both dot blot hybridization and direct sequencing method. Mutation of N-ras codon 61 may be significant in malignant transformation of follicular thyroid tumors. Because of its easy availability, the mutation-specific PCR method is a useful screening test for N-ras mutations.

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Aminoguanidine (AG) is a potential therapeutic agent for preventing the generation of advanced glycation end products in diabetes mellitus. In this study, the effect of AG on insulin secretion was investigated in in vitro rat pancreatic islets. The islets were aseptically isolated and cultured in fissure culture medium 199 for 48h with or without AG. After the culture, batches of 10 islets were incubated in Krebs-Ringer bicarbonate buffer containing 3.3mM or 16.7mM glucose. Islets previously exposed to 0.18mM AG or 0.45mM AG showed similar insulin release to control islets at a 16.7mM glucose concentration, but high glucose-stimulated insulin release was inhibited in the islets exposed to 1.8mM. In the perifusion experiment, insulin release caused by 16.7mM glucose from the islets previously exposed to 1.8mM AG was not significantly different from that of the control islets. However, culture of the islets with higher AG concentrations, 4.55mM and 9.1mM, significantly inhibited glucose -stimulated insulin release (<0.02 and 0.002, respectively). These results suggest that AG at high concentrations impairs pancreatic B-cell response to a high concentration of glucose.

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We report a case of benign symmetric Lipomatosis with hypothyroidism. Functional abnormalities and distribution of lipomas in benign symmetric lipomatosis suggest that the lipomas in this disorder may represent brown adipose tissue. In conditions where mRNAs of uncoupling protein, which is believed to be unique for brown adipose tissue mitochondria, were detected in one μg of poly (A⁺) rat brown fat RNA, no signal at all was found in the lipomatous tissue, suggesting that the masses of benign symmetric lipomatosis are not functional brown adipose tissue.

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Epidermal growth factor (EGF) modestly increased DNA synthesis by cultured rat granulosa cells. FSH also stimulated DNA synthesis dose-relatedly with the maximal effect occurring at FSH 100ng/ml. The stimulatory effect of FSH was still greater than that of EGF. However, in the presence of EGF, the stimulatory effect of FSH at any concentration was regulated to the level as high as when EGF alone stimulates. In addition, EGF inhibited DNA synthesis induced by forskolin, but enhanced the action of (Bu)₂cAMP additively, which indicates that EGF attenuates DNA synthesis of granulosa cells by suppressing the activity of adenylate cyclase or cAMP production. As it is suggested that CAMP is the most likely intracellular second messenger for FSH, the regulatory effect of EGF on FSH-induced DNA synthesis could be, in part, due to suppression of cAMP production. These results suggest that EGF is involved in granulosa cell proliferation, irrespective of the presence of FSH, in a different pathway from FSH and additionally modulates the FSH growth-promoting effect as a local regulator. The interaction between EGF and FSH may be important in the control of follicular development.

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To assess the prevalence of postpartum onset of disease among the patients with Graves' disease, we performed a retrospective examination of 289 consecutive female patients with Graves' disease who attended our thyroid clinic. Of these patients, 92 were female of child-bearing age (20-39 y.o.) who have had one or more deliveries, and at least 37 patients revealed clear evidences of postpartum onset of the disease. That is, at least 40% of Graves' patients of 20-39 y.o. developed their disease during the postpartum period.

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