A 76-year-old female patient who had been taking vitamin D₂ 100, 000U/day for more than 14 years due to hypoparathyroidism following total thyroidectomy was admitted because of protracted hypercalcemia.
On admission, the levels of serum vitamin D₂ (99.8ng/ml) and 25-OHD₂ (356ng/ml) were very high, and 1, 25-(OH)₂D₂ was low (4.0-18.7pg/ml). Serum D₃, 25-OHD₃ and 1, 25-(OH)₂D₃ were below the normal range. Despite intensive hydration with saline, intravenous hyperalimentation with phosphate-and calcium-free nutrients, and administration of glucocorticoid and calcitonin, the hypercalcemia persisted, accompanied by hypoproteinemia, edema, pleural effusion and congestive heart failure. The serum D₂ and 25-OHD₂ concentrations remained high and were accompanied by a gradual increase in 1, 25-(OH)₂D₂ (121pg/ml), which further increased after the administration of bisphosphonate (pamidronate) to 183pg/ml. Seventeen months later, serum calcium and 1, 25-(OH)₂D₂ were normalized but serum D₂ and 25-OHD₂ remained high. The serum 24, 25-(OH)₂D₂/25-OHD₂ ratio was relatively constant throughout her clinical course, whereas the low serum 1, 25-(OH)₂D₂/25-OHD₂ ratio at admission gradually increased during admission, suggesting that the increase in serum 1, 25-(OH)₂D₂ is due to increased production rather than decreased degradation. The administration of pamidronate further increased serum 1, 25-(OH)₂D₂.
These features of the clinical course demonstrate that the 1, 25-dihydroxyvitamin D concentration in hypercalcemic patients with protracted vitamin D intoxication may be decreased, normal or increased. Possible factors responsible for a protracted increase in serum 1, 25-(OH)₂D₂ are body weight loss, hypoproteinemia, and phosphate depletion. In addition, some bisphosphonates would certainly promote PTH-independent production of 1, 25-(OH)₂D₂.

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A fifteen-year-old male was admitted to our hospital because his thyroid function showed a lack of TSH suppression in the face of elevated thyroid hormone. This patient complained of heat intolerance, palpitation and hand tremor. Peripheral indices of thyroid hormone action indicated a hypermetabolic state. Serum TSH did not respond sufficiently to TRH stimulation, suggesting TSH-secreting pituitary adenoma. However, sellar CT scan and MRI images did not demonstrate any pituitary adenoma. Moreover, the serum TSH α-subunit concentration was not high and serum TSH was partially suppressed by the administration of T₃. Furthermore, the results of single stranded conformation polymorphism (SSCP) suggested the existence of mutation(s) in the exon 7 of T₃ receptor β (TRβ) gene of this patient. These findings support the diagnosis of pituitary resistance to thyroid hormone.

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Various aspects of the way of life in 20 adult patients (mean age: 25.7±6.0) with Turner syndrome were studied for their quality of life (QOL). The study found that many more Turner women went on to university (P<0.01) than the general population, whereas GH-deficient women did not. The employment status of both Turner and GH-deficient women does not differ from that of the general population. Only 7 of the 12 Turner and 5 of the 15 GH-deficient employees are satisfied with their present jobs, but 10 of the former and 7 of the latter women think that their jobs are worthwhile. The total annual income of 3 of 19 Turner women exceeded 3 million yen, but not that of any of 10 GH-deficient women who answered the question on their income. Half of the Turner and GH-deficient women complained of shoulder stiffness and one fourth of the Turner and one fifth of the GH-deficient women have a sense of despair and irritability. Seven Turner and 9 GH-deficient women have anxiety about their body, and 6 of the former and 8 of the latter have anxiety about marriage. Only 4 Turner and 3 GH-deficient women are married. Three of the former marriages were arranged by their parents, but all 3 GH-deficient women got married after falling in love. These marriage rates are significantly lower (P<0.005) than that of the age-matched general population. Most of the unmarried women in both groups live with their parents, and half of the Turner and one third of the GH-deficient women have difficulty in getting clothes and shoes to fit them. Otherwise, they have no particular problem in their daily life. In conclusion, Turner women are well educated and work as normal women, but they, as well as GH-deficient women, appear to be anxious about their body and marriage.

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It seems reasonable to expect that biochemical changes occurring in the pregnant woman with diabetes should be reflected in the placenta structure. However, it has not been possible to correlate placental morphology with glycemic control in a comparison between those with long life diabetes and poorly controlled gestational diabetes. In the present study we have histologically studied the syncytiotrophoblast of human placentae from overt diabetic and poorly controlled gestational diabetic patients. Using specific staining techniques and direct light microscopy we qualitatively studied these placentae and compared them with the normal placentae. We found fibrin thrombi, villous oedema, hyperplasia and thickening of basement membrane in the placentae of poorly controlled gestational diabetic mothers. Direct microscopy revealed that these various changes in syncytiotrophoblast structure were marked in the poorly controlled gestational placenta compared with overt diabetics, and could have been due to the presence of histochemical compounds e.g. general carbohydrates and lipids. These studies may indicate that poor control of diabetes during the gestation as indicated by high level HbAlc may result in the accummulation of carbohydrate compounds and fat droplets in the placental basement membrane, leading to structural changes in the placental cells.

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This study was designed to investigate the therapeutic efficacy of estrogen in female patients with dementia of the Alzheimer type (DAT). Fifteen DAT patients with a mean age of (x±SE) 71.9±2.4 years were treated with 0.625mg of conjugated equine estrogens orally twice a day for 6 weeks. Of the 15 DAT patients, 4 were diagnosed as mild, 7 as moderate and 4 as severe. The effects of estrogen on DAT patients were evaluated by psychometric assessments, behavior rating scales, regional cerebral blood flow (rCBF) measurement and quantitative EEG analysis. Psychometric assessments consisted of Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale (HDS). Dementia syndromes were evaluated by the CBS-Scale (GBSS) and Hamilton Depression Rating Scale (HDRS). During estrogen replacement therapy (ERT), the mean MMSE score (x±SE) increased significantly from 11.6±1.9 to 13.2±2.0 at 3 weeks (P<0.01) and 13.8±2.0 at 6 weeks (P<0.001). The mean HDS score increased significantly from 8.6±2.1 to 11.5±2.3 at 3 weeks (P<0.001) and 11.6±2.6 at 6 weeks (P<0.01). Significant improvements in the mean scores of the GBSS and HDRS were also observed in the estrogen-treated group, but not in the untreated control group with a mean age of 71.2±2.5 years (n=15). The rCBF was measured by single photon emission computed tomography (SPECT). ERT increased the mean rCBF significantly in the lower frontal region (P<0.01) and primary motor area (P<0.02) of the right hemisphere. The mean absolute power delta band values in both left and right frontal EEG (Fp₁ and Fp₂) (P<0.01) and theta₁ band values in Fp₂ (P<0.05) decreased significantly during ERT. It is inferred that ERT significantly improves cognitive functions, dementia symptoms, regional cerebral blood flow and EEG activity in female patients with DAT.

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Two cases of asymptomatic adrenocortical insufficiency are reported. Both patients had a normal cortisol and increased ACTH. The cortisol response to ACTH was impaired, although not absent, in both cases. One case was associated with autoimmune polyglandular syndrome type II (Graves' disease and vitiligo), and the other was possibly associated with an early stage of Hashimoto's thyroiditis, suggesting autoimmune pathogenesis of their adrenocortical insufficiency. CT of the abdomen revealed unilateral enlargement of the adrenal glands in one case, but no enlargement of the adrenal glands in another case. Adrenal hypofunction seemed to be compensated for by increased trophic hormone (ACTH), as in subclinical hypothyroidism. However, prolonged ACTH stimulation increased urinary 17-OHCS in both cases, and normalized cortisol response to ACTH in one case. In both cases, the plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were normal, and adrenal autoantibodies were negative, suggesting that neither negative adrenal autoantibodies nor normal PRA can exclude asymptomatic adrenocortical insufficiency. The results suggest that a rapid ACTH test should be performed in cases with increased ACTH, especially those associated with other autoimmune endocrine disorders.

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We treated two patients with Schmidt's syndrome who showed some differences in the endocrinological findings in adrenal steroidogenesis. However, there had been no reports describing in detail which zone(s) is most usually destroyed in the adrenals in Schmidt's syndrome of which the pathogenesis is thought to be intimately related to immunological disturbances. Case 1 is a 63-year-old female, presenting a complete deficiency of almost all adrenal steroids. Case 2 is a 53-year-old female, showing a partial deficiency of adrenal steroids, and examination of various plasma adrenal steroids suggests that impairment of the zona fasciculata may be mainly confined to the adrenal cortex. The results of aspiration biopsy cytology of the thyroid demonstrated the presence of chronic thyroiditis in each case. Case 2 also presented empty sella detected by MRI of the pituitary gland. It is therefore suggested that zona fasciculata cells may be first destroyed and the impairment seems to spread to all zones in the adrenals in Schmidt's syndrome. Moreover, some patients with Schmidt's syndrome may have empty sella.

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We have isolated a cDNA encoding a novel placental lactogen (PL), PL-I mosaic (PL-Im), by screening the cDNA library in λZAP of the mid-pregnant (day 12) rat placenta. The cDNA comprised an open reading frame of 687 by encoding 229 amino acids, in which there were two putative N-glycosylation sites. Northern blot analysis showed that PL-Im mRNA was expressed specifically during mid-pregnancy (days 10 and 12) in the rat placenta. The cDNA was highly homologous with those of other rat PL family members; in particular, the homology among PL-Im, PL-I (mid-pregnancy-specific) and PL-Iv (late-pregnancy-specific) was over 90%. Interestingly, the nucleotide sequence of PL-Im cDNA was a mosaic of PL-I and PL-Iv and it did not possess its own particular sequence. As the genomic pattern determined using Southern blot analysis of PL-Im was distinct from that of PL-I and PL-Iv, the encoded area of PL-Im appears to be independent of those of PL-I and PL-Iv on the gene. In the dendrogram of the rat PL family constructed on the basis of the nucleotide sequence homologies, PL-Im was located between PL-Iv and PL-I in the process of molecular evolution. Therefore, PL-Im has a unique cDNA structure and may be a principal factor in the molecular evolution of PLs.

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We established a cell line (hPTC) from the tissue of papillary thyroid cancer surgically excised from a 27-year old female patient. Synthesis of cAMP by the hPTC cells was stimulated by TSH. This cell line has continued to divide as a monolayer in a tissue culture for three years. We assessed growth regulation of the hPTC cells by protein tyrosine kinase and cAMP-dependent protein kinase by measuring the DNA content of the hPTC cells in 24-well plates with 3, 5-diaminobenzoic acid after incubation in various growth factors. Basic fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin-like growth factor-1 (IGF-1), all of which bind to their respective receptors with tyrosine kinase activity, stimulated DNA synthesis in the hPTC cells. Neutralizing antibodies to basic FGF and EGF suppressed the growth stimulation by basic FGF and EGF, respectively. Genistein, a specific protein tyrosine kinase inhibitor, inhibited proliferation of the hPTC cells. On the other hand, thyrotropin, dibutyryl cAMP (dBC) and forskolin inhibited proliferation. KT5720, a specific cAMP-dependent protein kinase inhibitor, restored the growth of the hPTC cells even in the presence of dBC. This study shows that stimulation of the protein tyrosine kinase activity by basic FGF, EGF, and IGF-1 promoted DNA replication by the human thyroid cancer cell line. However, activation of the cAMP-dependent protein kinase inhibited proliferation of this cell line.

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To evaluate the physiological significance of inhibin in various types of amenorrhea, serum immunoreactive (IR)-inhibin levels were measured and compared with those in normal cycling women. Amenorrheic women were as follows: (1) 23 women with PCOD, 11 women with hypogonadotropic amenorrhea (HA, n=23) and 11 women with regular menstrual cycles. Women with HA were further divided into 2 groups according to the presence or absence of withdrawal bleeding (WDB) after progesterone administration. HA with WDB was categorized as HA1, while HA without as HA 2. Serum IR-inhibin levels in women with PCOD were significantly higher than those in HA 2 and normal women at days 2 to 5 from the onset of menstruation and significantly lower than those in normal women in the mid-luteal phase. A significant positive correlation was obtained between IR-inhibin and FSH in HA 2 (r=0.681) and HA 1 (r=0.658), but no significant correlation between these two hormones in PCOD and normal women. These results indicated that basal IR-inhibin levels vary with types of amenorrhea. High IR-inhibin levels in PCOD patients suggest that inhibin plays a part in the discordant gonadotropin secretion in these patients.

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We previously reported that a blockade of GnRH receptor activation inhibited the already-initiated C-kinase pathway(s). We tried to investigate whether this finding is a general phenomenon or not. In this study, we employed three GnRH antagonists, [D-Phe², Pro³, D-Phe⁶]-GnRH, [Ac-D-Nal-Ala¹, D-pCl-Phe², D-Ser(Rha)⁶]-GnRH, and [Ac-D-p-Cl-Phe^{1, 2}, D-Trp³, D-Lys⁶, D-Ala¹⁰]-GnRH (referred to as #1-, #2-, #3-GnRH antag., respectively). Each antagonist was examined for its potency against GnRH by analyzing its inhibitory effect on LH release from pituitary gonadotrophs as well as on the increase in the cytosolic Ca²⁺ concentration. As a result, the #1-GnRH antag. was found to be weaker than the other two compounds. Consistent with a previous study, the #3-GnRH antag. inhibited the action of TPA on LH release. However, independently of their potency as GnRH-antagonists, the two other antagonists had no inhibitory effect on TPA-induced LH release. While it is generally accepted that the C kinase pathway plays a major role in the GnRH-induced LH release, not all GnRH antagonists can inhibit LH release by blocking the already-activated C kinase system.

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19-Hydroxyandrogens are known to be an intermediary metabolite in the aromatizing reaction, though the physiological role of this compound has not yet been clarified. In this study, microsomes obtained from human corpus luteum were incubated with testosterone or 19-hydroxytestosterone (19-OHT) as the substrate to investigate the biochemical significance of 19-OHT in the process of aromatization in the ovary. The inhibitory effects of 4-hydroxyandrostenedione (4-OHA) on the formation of estradiol from testosterone and 19-OHT in human ovary were also investigated.
When testosterone was incubated with human ovarian microsomes, 19-OHT and estradiol were identified. When 19-OHT was used as the substrate, the formation of estradiol was demonstrated. To our knowledge, this is the first report to demonstrate the formation of estradiol from 19-OHT in human ovarian tissue. The Km value of aromatase for testosterone on human corpus luteum microsomes was 0.21μM. 4-OHA exhibited inhibition with a Ki of 35nM. With testosterone and 19-OHT as the substrate, the formation of estradiol was also equally inhibited by 4-OHA. A dose dependent inhibition of estradiol formation was observed, with no apparent accumulation of 19-OHT. These results suggest that 19-OHT may not only be an intermediary metabolite in the aromatization of testosterone by human ovary but could be a product of the microsomal enzyme.

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A 55-year-old woman developed Cushing's syndrome due to ACTH-independent bilateral adrenocortical macronodular hyperplasia. Plasma ACTH was undetectable, and was not stimulated by administration of metyrapone, CRH, or insulin. Hypercortisolism was not suppressed by a high dose of dexamethasone, but was responsive to ACTH. Both adrenal glands were enlarged with a total weight of 200g, and contained multiple nodules composed of two cell types (large clear cells and small compact cells). In immunohistochemical studies, P450c17 immunoreactivity was predominantly observed in small compact cortical cells, while that of 3βHSD was observed exclusively in large clear cortical cells. This pattern of expression of steroidogenic enzymes as well as histological and clinical features is considered to be unique to ACTH-independent bilateral adrenocortical macronodular hyperplasia.

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Seven patients with growth hormone (GH)-secreting pituitary adenoma were treated preoperatively with octreotide (Sandostatin or SMS 201-995; a somatostatin analogue), and were compared with 18 non-treated patients in their clinical courses and adenoma analyses. Octreotide treatment improved the endocrinological data in all 7 cases. The octreotide-treated adenomas were soft and easily removed by suction and curettage. The postoperative normalization of endocrinological data was encountered more often in the octreotide-treated cases than in the non-treated, although the statistical significance was not observed by the limited number of cases. The adenoma tissues were examined with conventional histology and immunohistochemistry, and the amount of GH messenger ribonucleic acid (mRNA) was quantitatively assessed. The studies demonstrated: 1) No fibrosis nor necrosis was observed in the adenomas from the octreotide-treated patients. 2) Immunohistochemistry for human GH revealed no remarkable differences between the octreotide-treated and the non-treated adenomas. 3) The amounts of GH mRNA in the adenoma from the octreotide-treated patients were 4.2±1.8 (mean± SEM; expressed in an arbitrary unit) and were significantly less than those from the non-treated (33.6± 9.1). These data suggest that octreotide inhibits not only GH release from the adenoma but also its biosynthesis.

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TZP-4238 is a new potent, orally active steroidal antiandrogen. Antiandrogenic activity and endocrinological profile of TZP-4238 were investigated in rats, except that progestational activity was determined in rabbits. TZP-4238 suppressed the testosterone propionate-induced increases in the weights of the ventral prostate, seminal vesicle and levator ani in castrated immature male rats. TZP-4238 also decreased the weights of the ventral prostate, seminal vesicle and levator ani in intact adult male rats, but did not affect the weight of the testis or the serum concentrations of luteinizing hormone and testosterone. TZP-4238 did not have such an inhibitory effect on the weight of the adrenal gland as seen in other steroidal antiandrogens. It exhibited potent progestational activity. Although TZP-4238 did not exert androgenic or estrogenic activity, it had weak antiestrogenic activity. These results suggest that TZP-4238 exerts an antiandrogenic effect on the prostate without any compensatory change in the serum concentration of luteinizing hormone or testosterone in rats, and it is a useful drug for the treatment of androgen-dependent diseases such as prostatic hypertrophy and prostatic cancer.

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We reported earlier that the plasma level of corticotropin-releasing hormone (CRH) remained high 120min after the onset of such strong sustained stress as ether-laparotomy or water immersionrestraint, which reflected the persistent secretion of CRH from the hypothalamic median eminence (ME). We investigated the change in plasma CRH during water immersion-restraint stress in rats bearing an anterolateral cut around the medial basal hypothalamus (MBH) which cuts the CRH neurons from the PVN to the ME. Concentrations of CRH in the hypothalamus, extrahypothalamic tissues and peripheral blood were measured by radioimmunoassay. Plasma ACTH was measured with an immunoradiometric assay kit. Plasma baseline ACTH and CRH concentrations did not differ significantly in the sham vs. cut groups. At 120min after the onset of stress, plasma ACTH concentrations were definitely higher in both groups. In the cut group, plasma CRH at 120min after stress did not differ significantly from the baseline level, whereas plasma CRH at 120min was definitely higher in the sham group. Baseline CRH concentrations in the ME did not differ greatly in the two groups. CRH concentrations in the ME of both groups had decreased appreciably 120min after the onset of stress as compared with baseline CRH, and the CRH decrease was greater in the cut group than in the sham group. CRH in the neurointermediate lobe (NIL) and adrenal gland of both groups showed no significant change at 120min, compared with the control. These findings confirm that the continuous CRH increase in plasma during sustained stress is derived mainly from the hypothalamus. It is possible that the ACTH increase at 120min in the cut group depends not only on the secretion of pooled CRH in the ME but also on other ACTH-stimulating factors from peripheral tissues.

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A 51-year-old woman with Cushing's disease associated with adrenal myelolipoma is reported. A further characteristic feature was the coexistence of bilateral adrenal calcification and thyroid cancer. Previously several cases of adrenal myelolipoma associated with endocrine dysfunction were reported. The combination of Cushing's disease and adrenal myelolipoma has only been described in two cases of recurrent Cushing's disease but never in an initial occurrence of Cushing's disease. Continued stimulation by excessive adrenocorticotropic hormone (ACTH) not only developed adrenal hyperplasia but also might be involved in the pathogenesis of adrenal myelolipoma.

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A family with hereditary high serum thyroxine-binding globulin was studied. All the subjects studied were clinically euthyroid without goiter. The propositus (female), her mother and sister had high TBG, total T₄ and total T₃ with normal free T₄, free T₃ and TSH. Her father's thyroid function was within the normal range. Possible etiologic factors causing secondary hyper-TBG-nemia were ruled out in all the affected subjects. Isoelectric focusing demonstrated qualitatively normal microheterogeneity, ruling out possible TBG variations caused by liver diseases, estrogen therapy or pregnancy. Although the mechanism involved in the TBG increase awaits further investigation, it could be an abnormality in the gene controlling the synthesis of TBG.

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