In order to clarify an alteration in thyroid functions in patients with chronic liver diseases, serum total and free thyroxine (T₄, FT₄), total and free triiodothyronine (T₃, FT₃), total reverse T₃ (rT₃), thyrotropin (TSH), thyroxine-binding globulin (TBG) concentrations, and T₃uptake (T₃U) were measured by radioimmunoassays in 53 patients with chronic hepatitis (CH), 24 patients with compensated liver cirrhosis (LC), 17 patients with hepatocellular carcinoma associated with LC (HCC), and 40normal subjects. Serum T₄, T₃, and rT₃in CH, and serum rT₃in HCC were significantly increased, while serum T₄in LC and serum T₃in HCC were significantly decreased. Serum TBG was increased and T₃U was decreased in these patients. Serum TBG in CH and LC correlated positively with transaminase, and inversely with prothrombin time. FT₄ and T₄/TBG ratios in CH and LC and FT₃and T₃/TBG ratios in LC and HCC were significantly decreased. Although T₄/TBG ratios in HCC and T₃/TBGratios in CH were significantly decreased, FT₄in HCC and FT₃ in CH were not decreased. The ratio of rT₃/T₃in CH and LC correlated with various liver function tests. FT₃ in LC and HCC correlated inversely with BSP (45') and positively with KICG.No differences in serum TSH values were found between chronic liver diseases and normal subjects. From these results, it was concluded that the thyroid functions in patients with chronic liver diseases were affected by thedecrease in serum thyroxine, elevated serum TBG, the degree of which is in proportion to that of the liver cell damage, and impaired peripheral conversionof T₄to T₃, the degree of which is in proportion to that of the hepatic dysfunction.

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This paper describes a middle-aged man in whom an adrenal mass was incidentally discovered by upper abdominal echogram. Physical examination revealed no signs of Cushing's syndrome. The plasma cortisol level at 0800h was within the normal range, but the diurnal rhythm had disappeared. Plasma ACTH was undetectable throughout the whole day. Urinary 17-OHCS was slightly increased and was not suppressed by 2mg or 8mg dexamethasone. Metyrapone test and CRF test revealed no response. Aleft adrenalectomy was performed and histological diagnosis of the removed tumor was an adrenal adenoma. After operation, oral steroid supplementation was necessary. These data suggest that the autonomous cortisol secretion by the tumor accounted for all his daily cortisol secretion, but it was too small to be clinically functional. We propose that every patient with an incidentally discovered adrenal mass should be subjected to endocrinological evaluations.

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A girl, 12 years of age, developed Graves' disease compounded with rheumatic fever and idiopathic thrombocytopenic purpura. Thrombocytopenia improved under short-term treatment with steroids and her mitral valvular insufficiency, due to the rheumatic fever, disappeared 4 years later. Initially, she had been treated with propylthiouracil (PTU) for 28 months. She suffered a relapse 9 months after stopping PTU and so she was given further PTU therapy. However, hypothyroidism developed 11 months after the initiation of therapy and continued, though further PTU treatment was discontinued. She now receives 1-thyroxine and maintains a euthyroid state.
At the onset of the patient's hyperthyroidism, the TSH-binding inhibitor immunoglobulin (TBII) and the thyroid stimulating antibodies (TSAb) were found to be positive. During the remission period, only the thyroid stimulation blocking immunoglobulin (TSBI) was weakly positive. At relapse, only TBII was mildly positive. When hypothyroidism developed, both TBII and TSBI were positive, and TSAb was negative in all testings of her diluted IgGs.
The patient's TBII and thyroid dysfunction were unaffected by high-dose intravenous gammaglobulin therapy or by treatment with prednisolone 0.5 mg/kg/day for 2weeks.
In conclusion, the emergence of TSBI during or after anti-thyroid drug therapy might possibly lead to hypothyroidism in patients with Graves' disease.

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The effects of testosterone administration on testicular inhibin content and histology were studied in bilaterally cryptorchid rats, in which a marked decrease in testicular inhibin content had been observed. Mature male Wistar rats weighing approximately 300g were made bilaterally cryptorchid by placing the testes in the abdominal cavity. Testosterone in oil, 0.1, 1.0 or 10mg, was given i. m. eachweek. Testicular inhibin and testosterone content, histology and plasma LH, FSH and testosterone were studied 2 weeks later. Abnormally decreased testicular inhibin in cryptorchidism was restored toward normal by testosterone in a dose dependent manner in 2 weeks after surgery. Sertoli cell structure also recovered toward normal with increasing amount of testosterone. Decreased testicular testosterone content and Leydig cell atrophy were observed with suppressed plasma LH and FSH after testosterone. These results showed that the increased plasma concentration of testosterone had a stimulatoryeffect on the Sertoli cell function in cryptorchidism, in which compensated Leydig cell failure was demonstrated.

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As a part of studies concerning clinical application of the measurement of urinary iodide with an iodide-selective ion electrode, we report here the reference values for the iodide content or concentration in morning spot urine specimens from normal subjects of varying ages and studies with patientswith thyroid diseases in Japan. The number distribution of the iodide content or concentration in the morning specimens appeared logarithmic normal in adults, children and infants. Normal ranges foundin 95 per cent of populations of healthy subjects were 5.3 to 62.0μEmoles/g Creatinine (Cr) for adults, 5.3 to 42μmoles/g Cr for children, and 1.9 to 56μM for infants, respectively. Urinary iodide concentrations in breast-fed infants varied widely compared with those in bottle-fed infants. Mean values were 16.4μM for breast-fed infants and 8.6μM for bottle-fed infants, and they were not statistically different. Urine samples from the infants with transient hypothyroidism, who had undergone amniofetography showed extraordinarily high iodide concentrations, even though they were measured at 20th, 29th and 30th days after birth. Although urinary iodide excretion in patients with simple goiter was within normal limits, the mean was statistically lower than that in normal controls (p<0.001). Because of the simplicity and rapidlity of the electrode method, we strongly recommend it for usein examining iodide excretion in patients with various thyroid diseases.

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Changes in canine plasma glucose, immunoreactive glucagon (IRG), pancreatic polypeptide (PP) and insulin (IRI) were studied during the acute development of diabetes mellitus after iv alloxan injection. 10 mg or 75mg/kg body weight of alloxan was injected iv and blood was taken successively till one or two days later. Plasma glucose showed four phases: first immediate and moderate decreaseappeared 30 min after injection, second initial hyperglycemic phase, third hypoglycemic and fourth diabetic ones. Plasma IRIhadalready increased to 182±60μU/ml 10 min after injectionand again began to increase after about 6 h, peaking to 134±49μU/ml at 18 h. Plasma IRG began increasinggradually soon after alloxan injection. The initial value was 196±26pg/ml and it increased to 534±144pg/ml at 4 h during the initial hyperglycemic phase, then reached a higher level through the hypoglycemic and diabetic phases. The change in plasma PP was similar to that in IRG. The initial value was 256±95 pg/ml at 12 h after injection, peaking to 840±100 pg/ml in the hypoglycemic phase. Similar blunted values were obtained following 75mg/kg alloxan injection.
Thus not only plasma IRI but also plasma IRG and PP varied greatly during the acute development of alloxan diabetes and somecontribution of IRG to the initial hyperglycemic phase was suggested.

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Cerebrospinal fluid (CSF) and plasma levels of luteinizing hormonereleasing hormone (LHRH) were measured by RIA in 46 patients with acute intracranial diseases, ie, cerebral bleeding (group A), cerebral thrombosis (B), head injury (C) and meningitis (D), and the results were compared to those obtained in 21 patients with non-intracranial diseases (group E; control).
Immunoreactive LHRH concentrations in CSF (CSF IR-LHRH) of 8 postmenopausal women in group E ranged 1.3 to 6.1 (mean±SE: 3.1±0. 6) pg/ml, and those of 5 other women and 8 men with group E ranged 1.0 to 5.6 (3. 6±0.4) pg/ml. In 7 out of 15 patients in group A (7/15), CSF IR-LHRH were above the levels seen in group E. In group B, Cand D, CSF IR-LHRH were above the control levels in 9/15, 1/9, 3/7, respectively. The changes in plasma LHRH were not clear in postmenopausal patients in groups A and B. Plasma IR-LHRH in other women and men in group A were above the control levels in 2 out of 9 natients (2/9). Those in groups B, C and D were above thecontrol levels in 3/8, 1/9, 2/7, respectively. Moreover, both plasma and CSF IR-LHRH of 13 patients in group A or B in chronic stage were within the control ranges. In cases observed followingthe time course, the occasionally increased IR-LHRH in plasma and CSF tended to decrease following the abatement of the diseases. These results indicate that the presence of IR-LHRH in CSF is confirmed, and, in acute brain damage, the IR-LHRHIevels of CSFand plasma are occasionally elevated abnormally as a feature of one of the brain peptides.

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We recently purified luteinizing hormone (LH)-isoforms with renotropic activity from ovine pituitaries based on the stimulation of [³H] thymidine incorporation into renal DNA of castrated-hypophysectomized rats. In this study, we examined the hormonal interactions between ovine growth hormone (GH) and this LH-isoform in renal DNA synthesis. A single injection of LH-isoform (40μg) significantly increased [³H] thymidine incorporation, but an injection of GH (200μg) did not, during experimental periods of upto 26 hours. Repetitive ovine GH treatment (5 days) did not change basal [³H] thymidine incorporation, either, although its biological activity was evidenced by an increase in insulin-like growth factor-I (IGF-I). Stimulated [³H] thymidine incorporation byLH-isoform (100μg) was significantly suppressed by an injectionof GH (200μg) and was, to a greater extent, by repetitive treatment with GH (200μg/day, for 3 or 5 consecutive days). These results demonstrated one example of the effect of complex hormonalinteractions on kidney growth.

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Basal levels of sex steroids, and the responses of LH and FSH toLH-RH were studied in twenty-five female patients with Cushing'ssyndrome (17 Cushing's disease and 8 adrenocortical adenoma). Only two patients had a regular menstrual cycle. Amenorrhea or oligomenorrhea had been of long duration in the other cases except for three postmenopausal patients. In patients with Cushing's disease, basal estradiol was low or below normal in 86%. Progesterone was normal in 83%, but testosterone was high in half of the cases. The response of LH to LH-RH in patients with Cushing's disease was normal in 35%, low in 35% and high in 29% of the cases. FSH response to LH-RH was normal in 23.5%, low in 23.5% and high in 53%. In patients with adrenocortical adenoma, basal of estradiol was low or below normal, but progesterone and testosterone were normal in all cases. The response of LH and FSH to LH-RH in all patients with adrenocortical adenoma was higher than normal. In three postmenopausal women, a higher response of LH and FSH to LH-RH was seen in two cases and suppressed in one case. These data suggest that the main site of suppression of the gonadal axis in patients with adrenocortical adenoma is the gonad rather than the pituitary gland or hypothalamus, though the mechanism of hypogonadism in patients with Cushing's disease is heterogeneous.

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To elucidate the molecular mechanism of rat thymus involution induced by administration of glucocorticoid, we screened a cDNA library for polysomal poly (A) ⁺RNA from adrenalectomized rat thymi by a differential colony hybridization method. Labeled cDNAs for mRNAs isolated from thymi of adrenalectomized rats and rats receiving dexamethasone (Dex) treatment were used as probes. Eight cDNA clones for mRNAs which had a diminished response to administration of Dex were isolated. The relative concentration of cloned mRNAs in the thymic polysomal RNA was significantly decreased 3 h after hormone administration, while changes in the nuclear RNA were not significant after Dex administration. One of the selected cDNA clones designated pRTGR-8 corresponded to mRNA of about 3, 000 nucleotides, and a nuclear run-off transcription assay indicated that the rate of transcription of pRTGR-8 RNA was repressed by Dex administration. The cloned cDNAs obtained in this experiment may provide useful probes for studying the negative regulation mechanism of gene expression by glucocorticoids.

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Functionally active or regressing luteal cells were obtained from pseudopregnant (psp) rats between days 5-8 of psp or on day 15 of psp, respectively. They were monolayer-cultured (10⁶/dish) in the presence of 0.2μg/ml LH 2.0μg/ml PRL and 10μg/ml pregnenolone for 4 days with or without macrophages, and their progesterone and pregn-4-en-20α-ol-3-one (20α-OH-P), a nonactive progestin, secretion was examined. In the culture without macrophages, although functionally active luteal cells secreted progesterone dominantly during day 1 of culture (Day 1), the amounts of progesterone and 20α-OH-P secreted were inverted on Day 2, and the dominance of 20α-OH-P continued from Day 2 to Day 4. In the functionally regressing luteal cell culture, more 20α-OH-P than progesterone was secreted throughout the culture period.
The addition of peritoneal macrophages (2.5×10⁶) to the active luteal cell monolayer lengthened the dominance of progesterone secretion for an additional day and the inversion occurred on Day 3. The progestin ratio (progesterone/20α-OH-P) on Day 2 was maintained significantly higher. The daily addition of macrophages maintained the progesterone dominance throughout the culture period. On the other hand, macrophages had no effect on luteal cells already functionally regressing.
These results indicate that macrophages are effective in maintaining the progesterone secreting activity of luteal cells in vitro.

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In order to elucidate the mechanism of postpartum aggravation of autoimmune thyroid disease (AITD), we serially examined the change in the proportion of peripheral large granular lymphocytes (LGL), which have activities of NK, K and/or cytotoxic T cells, in their postpartum period. Within 6 months postpartum, the percentage of LGL increased transiently in patients with AITD who remained euthyroid, or developed destructive thyrotoxicosis and/or hypothyroidism due to thyroiditis and even in normal controls. These changes in the LGL percentage were more obvious in the patients who had marked postpartum thyroid dysfunction. In contrast, we did not find a definite increase in the LGL percentage within 6 months postpartum in patients with Graves' disease who relapsed into Graves' thyrotoxicosis. These deta suggest that the increase in LGL in the postpartum period may be related to the induction of postpartum destructive thyrotoxicosis and/or hypothyroidism in AITD.

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It has been observed that basal and/or TRH-stimulated serum TSH levels occasionally conflict with the actual values of circulating thyroid hormones in patients with anorexia nervosa. In the present study sixteen female patients with anorexia nervosa during self-induced starvation displayed clinical findings suggesting hypothyroidism, e.g., cold intolerance, constipation, bradycardia, hypothermia and hypercholesterolemia in association with decreased serum total T3 (62.8<5.2ng/dl) and T4 (6.6<0.3μg/dl). Markedly decreased T3 correlated positively with average heart rate (r=0.5655, P<0.025) and negatively with total cholesterol (r=-0.7413, P<0.005). This result may suggest that peripheral metabolic state of the underweight anorexics depends considerably upon the serum T3 concentration.
Despite decreased total thyroid hormones, free T4 assayed by radioimmunoassay was normal in all five cases examined (1.4<0.2ng/dl) and the free T4 index in fifteen cases was normal except in one case. Basal TSH was not increased and TSH response to exogenous TRH was not exaggerated in any. These results may be compatible with a theory that free T4 has a dominant influence on pituitary TSH secretion. Furthermore, glucocorticoids may also have some influence on depressed TSH response, because an inverse correlation between increased plasma cortisol and the sum of net TSH increase after TRH was observed in twelve cases examined.
In conclusion, it is suggested that normal sensitivity of peripheral tissues and pituitary thyrotroph to different circulating thyroid hormones is maintained in anorexia nervosa patients even during severe self-induced starvation, and that the metabolic state in these patients is considerably under the influence of circulating T3.

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To investigate the expression and the regulation of nuclear triiodothyronine (T₃) receptor at the gene level, cellular (c)-erb-A mRNA isolated from lymphocytes in patients with thyroid dysfunction was examined by Northern gel analysis and dot blot hybridization using viral (v)-erb-A cDNA probe. Human lymphocytes contained c-erb-A mRNA (approximately 2.0 kilobase (kb) in length), and c-erb-A mRNA, which was determined by dot blot hybridization, was observed to be increased in hypothyroid patients but unaltered in hyperthyroid patients. The high level of c-erb-A mRNA may contribute in part to the increase in nuclear T₃ receptor and these results suggest the presence of up-regulation of nuclear T₃ receptor at the gene level in the lymphocytes of hypothyroid patients.

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In our previous study, we observed a tendency towards an age-related increase in the serum thyrotropin (TSH) concentration. Regulatory mechanisms TSH secretion in elderly subjects were studied. In 43 elderly subjects, serum TSH did not correlate significantly with serum T₄, T₃ free T₄ or rT₃. Further, those with increased TSH (>5 mU/l, 9 subjects) did not overlap with those with low T₃ (<0.92 nmol/1, 8 subjects). Increases in serum TSH were not associated with the presence of circulating anti-thyroid autoantibodies.
A TRH test using a 500μg single bolus injection was performed in 15 subjects. TSH response (basal: 1.92±1.42 (s. d.) mU/1, peak: 11.25±5.33 mU/1, Σ: 26.74±12.89mU/1, respectively) did not differ significantly from that of younger subjects. T₃ response after TRH varied greatly and a close correlation was observed between basal T₃ and peak T₃ (r=0.86), and also between peak T₃and peak ΔT₃ (r=0.81). A significant correlation was observed between ΣTSH and basal T₃ (r=0.60). Neither plasma cortisol, epinephrine norepinephrine concentrations showed any significant correlation with basal and TRH-stimulated TSH or T₃concentrations. However, the plasma dopamine concentration correlated significantly with ΣTSH (r=0.60) and basal T₃ (r=0.52), respectively.
In conclusion, the increase in serum TSH observed in elderly subjects was felt to represent a physiological adaptation to maintain serum T₃. Low T₃subjects appear to have a disturbance in this mechanism, with decreased TSH and T₃ response to TRH stimulation. The details of this disturbance havenot been clarified, but a possible dopaminergic mechanism was suggested by the decreased plasma dopamine concentration observed in the low T₃ group.

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Plasma human growth hormone (hGH) profiles and biological activities of recombinant hGH were compared after im and sc injection in 8 normal volunteers. The time to reach maximal plasma GH and plasma hGH concentrations and the areas under the curve of hGH profiles did not differ significantly after im and sc injections. The biological effect of hGH in increasing nonesterified fatty acid and insulin-like growth factor-I (IGF-I) was the same after both im and sc injections.
During 6 months of daily sc administration of recombinant hGH in 20 naive patients, their height increased between 5 and 16.5cm with a mean of 11.0±3.0cm/year. In 27 patients who switched from hGH injections of 2-4 times/week to daily injections, the height increased between 5.3 and 16.5cm with a mean of 8.3±2.2 cm/year. These values were greater than those observed in a previous study in which the same amount of hGH was injected in 2-4 doses per week. Plasma IGF-I increased more with daily sc administration than with 2-4 doses per week. The rate of appearance of an antibody to hGH was low (0.5%) and there were no notable changes in blood cell count, urinalysis and/or routine chemistries during the 6 months of daily recombinant hGH treatment.
These results show that sc daily administration of hGH is safe, has a greater growth promoting effect, and can be recommended for the treatment of patients with GH deficiency.

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A patient with essential hypertension receiving the oral administration of acebutolol, aβ₁-selective adrenergic blocker, showed a marked increase in urinary 17-ketosteroid (17-KS) excretion determined by Zimmermann's method. Since the normal concentration of each fraction of 17-KS was found in this case by gas chromatography, the possibility of an abnormality in steroid metabolism could be excluded from the mechanism of the increase in the measured value for urinary 17-KS. In the urine samples from patients treated with acebutolol, acebutolol and acetylated acebutolol, a main metabolite acebutolol, were found equally among them. Moreover, acebutolol acetylated acebutolol resulted in a dose-dependent increase in 17-KS by Zimmermann's method in phosphate buffered saline or in a urine sample. However, the otherβ-blockers, such as propranolol, alprenolol and oxprenolol did not show any effect on the determined value for urinary 17-KS.
Thus it was concluded that the activated methylene group of acebutolol and acetylated acebutolol may interfere with the measured values obtained by Zimmermann's method.

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Human corticotropin-releasing hormone (hCRH) test was performed in 57 normal volunteers and 102 patients with hypothalamic, pituitary and adrenocortical diseases. Intravenous bolus injection of synthetic hCRH, 100μg for adults or 1.5μg/kg for children, increased plasma ACTH and cortisol levels in about 90% of normal subjects. In 47 patients with Cushing's disease, plasma ACTH tended to show an exaggerated response to hCRH and peak ACTH was the most frequent abnormal component among the several reaction parameters. Poor responders among normal subjects and patients with Cushing's disease had significantly higher plasma cortisol levels before CRH administration. Patients with hypothalamic hypopituitarism showed exaggerated response, whereas patients with primary pituitary lesion, isolated ACTH deficiency or adrenal Cushing's syndrome showed no ACTH response. These differences in the response of patients suggest the value of the hCRH test in their differential diagnosis.

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The authors reported a patient with a large prolactinoma (PRL 1, 716ng/ml) who was treated with bromocriptine for two years and followed up for a subsequent 36 months. After the start of the therapy, the tumor size was dramatically reduced, and finally the disappearance of the tumor was confirmed by high resolution coronal CT. The serum prolactin level and pituitary function were normalized. The tumor has not regrown and the blood prolactin level has remained normal for 36 months since the discontinuation of bromocriptine administration. This is a very rare case report on the eradicative effect of bromocriptine on such a large prolactinoma.
Another characteristic of this case was that the prolactin reserve was maintained not only before the therapy but also during the early stage of the therapy.

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Seminal vesicle cells of neonatally castrated adult mice show poor response to androgen, compared to those of mice castrated at adulthood; effects of pretreatment with androgen or estrogen at adulthood on androgen-induced proliferation of the seminal vesicle cells were examined in neonatally castrated mice. Male mice castrated at day 0 after birth were pretreated with daily injections of testosterone propionate (TP, 100μg/mouse), 17β-estradiol (E2, 5μg/mouse) or vehicle for 20 days starting from day 60; daily TP injections (100μg/mouse) for 30 days were started again from day 110 in all the pretreated mice to examine androgen-induced proliferation by incorporation of 5-[125I] iodo-2'-deoxyuridine into the whole seminal vesicles. Both TP and E2 pretreatments significantly increased the seminal vesicle weight found before TP treatment. However, androgen-induced proliferation of the seminal vesicle found in neonatally castrated mice (poor response; long duration witha low peak on day 3) was changed at least in part to that found in mice castrated at adulthood (good response; short duration with a high peak on day 3) only following the TP pretreatment but not at all following the E2 pretreatment. The E2 pretreatment induced poor androgen-induced proliferation with a low peak on day 7.

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In two patients with congenital isolated thyrotropin (TSH) deficiency, serum TSH determined by a sensitive immunoradiometric assay (IRMA) was consistently undetectable. The basal levels of serum free TSH-αsubunit (TSH-α) determined by a specific radioimmunoassay (RIA) were elevated in the hypothyroid state, and decreased to the undectable level during displacement therapy with thyroid hormone. The serum free TSH-αsignificantly increased following intravenous administration of thyrotropin releasing hormone (TRH). Serum free TSH-βsubunit (TSH-β) was undectable. These findings suggest that TSH deficiency in this disease is not due to absence of thyrotroph in the pituitary gland or deficiency of TSH-α, but to abnormalities of the TSH-βgene.

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