To elucidate the mechanism of suppression of prostaglandin (PG) production in decidua in early pregnancy, the PG synthetase activity of decidua and midsecretory endometrium was studied. The microsomal fractions and their supernatants were prepared from the tissue by ultracentrifugation at 105, 000g. The standard incubation mixture consisted of the microsomal fraction and ¹⁴C arachidonic acid with cofactors, with incubation being carried out for 10 minutes at 37°C. After extraction, the radioactivity of PGE₂ was measured and PG synthetase activity was assayed. The apparent Km value for PG synthetase in decidua was 4.6±0.14×10^-6 M (n=4), whereas that in endometrium was 4.6±1.18×10^-6 M (n=3). Subsequently, kinetic studies on PG synthetase inhibitor in decidua were carried out. When sheep seminal vesicle was used as an enzyme source, the decidual supernatant showed competitive inhibition. The inhibitory substance in decidua was inactivated after incubation for 15 minutes at 65°C. It seems likely that the suppression of PG biosynthesis in human decidua in early pregnancy is not due to the difference in PG synthetase found in decidua and in endometrium, but due to the existence of PG synthetase inhibitor in decidua.

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Desensitization of rat pituitary somatotrophs to human growth hormonereleasing factor (hGHRF) was investigated using cultured rat anterior pituitary cells. Growth hormone (GH) release decreased but the production of cAMP was still induced in response to subsequently added 10^-9 M hGHRF from cells pretreated with hGHRF at concentrations ranging from 10^-11 to 10^-7 M for 4h. Desensitization to 10^-9 M hGHRF was also observed in cells pretreated with 10^-9 M hGHRF for 4h in the presence of 2 mM EGTA, 10ng/ml nifedipine or 10^-9 M somatostatin-28, which decreased GH release during pretreatment. Forskolin and A23187. at concentrations of 10^-6 M and 10^-4 M, respectively, stimulated GH release from cells pretreated with hGHRF to the same extent as that from the control cells. These results, therefore, suggest that desensitization to GHRF occurs regardless of the presence of releasable GH pool and that some changes such as uncoupling of GHRF receptors with adenylate cyclase and decreased sensitivity to cAMP of cAMP-dependent protein kinase of the secretory mechanism of GH, in addition to the decrease in releasable GH pool and down regulation of GHRF receptors, may be involved in the desensitization mechanism.

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The effects of ovine corticotropin releasing factor (o-CRF) on plasma aldosterone, 18-OH-corticosterone (18-OHB), plasma adrenocorticotropin (ACTH) and cortisol were determined in eight patients with primary aldosteronism, six with aldosterone-producing adenoma (APA) and two with idiopathic hyperaldosteronism (IHA). The results were compared with those in six normal subjects and eleven patients with essential hypertension (EHT, 5with low renin and 6 with normal renin). In patients with APA, the peak plasma aldosterone and 18-OHB responses to 100μg iv of o-CRF (226%and 113% increase from baseline, respectively) were greater than those in EHT and normal subjects. The net integrated aldosterone and 18-OHB responses (840±156, and 419±121 ng/dl·hr, respectively) were also significantly greater (P<0.01) in APA than those in normals and EHT. In two patients with IHA, both the peak and net integrated aldosterone response were smaller than those in APA, in spite of nearly identical plasma ACTH and cortisol responses. These results suggest that augmented responses of mineralocorticoids to o-CRF may be characteristic of aldosteronism due to APA, mediated by CRF. induced ACTH, and possibly other proopiomelanocortin (POMC)-derived peptides.

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Serum total thyroxine (T₄), total triiodothyronine (T₃), T₄-binding globulin (TBG), free T₄ (FT₄) and free T₃ (FT₃) concentrations and the T₃-uptake (T₃-U) value were estimated in 11 patients with subacute thyroiditis, and compared with the same parameters in 11 patients with Graves' disease, whose serum T₄ concentrations were similar to the former group. Seven patients with subacute thyroiditis, who were treated with dicrofenac sodium alone, were investigated as to the sequential changes in serum parameters during their clinical courses.
The mean serum T₃-U value and FT₄, T₃ and FT₃ concentrations in patients with subacute thyroiditis were increased, but all were significantly lower than those in patients with Graves' disease (p<0.01, p<0.001, p<0.001 and p<0.001, respectively). Three patients with subacute thyroiditis, who showed shorter duration of symptoms than 10 days, had serum TBG excess. Thus the mean (±SD) serum TBG concentration (26.5±8.4 μg/ml) was significantly higher than that (18.3±2.9 μg/ml) in patients with Graves' disease (p<0.02). The ratios of serum T₃ to T₄ and FT₃ to FT₄ in patients with subacute thyroiditis were also significantly lower than those in patients with Graves' disease (p<0.001 and p<0.001, respectively). The serum FT₄ in 7 patients treated with dicrofenac sodium alone decreased to the normal range after 3 to 8 weeks from the onset of the illness. In 3 patients with TBG excess and one patient (TBG; 29.0 μg /ml), serum TBG declined in consequence of the serum FT₄ normalization. In 20 samples which showed a higher serum FT₄ level than 2.0 ng/dl, there was a significant and inverse correlation between serum TBG and the intervals from the onset of illness (r=-0.54, p<0.02).
These results indicate that in some patients with subacute thyroiditis the serum TBG increase induced by as yet unidentified factors may be found in the early phase of this disease, and that higher serum TBG in patients with subacute thyroiditis may contribute partly to the difference between serum T₃-U and FT₄ in subacute thyroiditis and Graves' disease despite a similar serum T₄ concentration.

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As reported previously, acute exacerbation of Hashimoto's thyroiditis shows quite unique histological findings, namely localized edematous inflammation. Similar histological characteristics and clinical manifestations were observed in 7 of 492 patients with Hashimoto's thyroiditis (A group). Their clinical and laboratory findings were compared with those of 15 cases with subacute granulomatous thyroiditis (S group). Age and sex distribution and goiters in A group were 39±21 years old (mean s.d.), 7/0 (F/M), and 6/1 (diffuse/nodular), respectively. These were somewhat different from those of S group (45±9, 12/3, and 3/12, respectively).
Thyroid functions in A group showed wide variation: 3 cases were euthyroid, 2 were mildly hypothyroid, and one was mildly thyrotoxic and one borderline thyrotoxic, and all of the S group patients were thyrotoxic. Their thyroid radiopertechnetate uptake, scintigraphy, duration from the onset till the first visit, and ESR and CRP values were also different from those of S group.
Clinical courses and outcomes of A group were generally favorable, but one of them finally underwent a total thyroidectomy. Per os and intrathyroidal administrations of steroid were effective, but there was observed a recurrence of symptoms in 3 cases. Finally, all 6 cases were left with diffuse goiters, 4 of them remaining euthyroid, and 2 falling into hypothyroidism.
The acute exacerbation of Hashimoto's thyroiditis is a rare complication, which is found to be different from subacute thyroiditis on histological, clinical and laboratory findings and is generally subtle. Steroid medication is considered to be the therapeutic choice but careful observation is necessary to avoid a recurrence.

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Canine pancreases divided into 8 anatomical subportions were examined for their regional insulin and glucagon content. Insulin content in the pancreas was gradually increased in the left lobe to about twice as much as that in the uncinatus, while glucagon content was increased steeply in the left lobe to 16 times as much as that of the uncinatus. Although hormonal content differs according to the anatomical area, a statistically significant positive correlation of mean regional insulin and glucagon content was observed (r=0.994, p<0.001). A constant ratio of these two hormones suggests the functional coupling of A and B cells within the islets or in a given pancreatic subportion.

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On account of recent reports suggesting that ovulation and luteinization involve immunological reactions, we examined the effect of splenectomy in rats on the recurrence of an estrous cycle. The spleen was removed from adult female rats at various times during an estrous cycle. A delay in ovulation was specifically induced in the rats splenectomized on the metestrous morning between 0700 and 0900 h. This delay in ovulation was reversed by an injection of splenocytes obtained either from estrous or metestrous donors, but not from diestrous or proestrous donors. The isolated splenic macrophage preparation mimicked the effect of splenocytes. Measurement of progestin levels throughout the estrous cycle suggested that the delay in ovulation was caused primarily by a delay in luteolysis; progesterone levels in ovulation delayed rats were higher and 20α-dihydroprogesterone levels were lower than those of intact rats on the diestrous day.
These results suggest that the macrophages in the spleen under the influence of endocrine milieu probably play a role in the recurrence of an estrous cycle by controlling luteolysis. The specific time of splenectomy to cause delay in ovulation will afford a new approach in analyzing the function of immunocytes in the ovary.

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Stage-specific initiation of milk synthesis was investigated in mice ovariectomized on days 7, 9, 11 and 13 of pregnancy, and the lactogenic response of the mammary gland was monitored by using the synthesis of casein, lactose content and PRL binding as parameters. Pregnant mice ovariectomized on day 7 or 9 showed no increase in these parameters 24 h after operation. After day 11 of pregnancy, a clear response was induced by ovariectomy, characterized by a low level of casein synthesis, small amounts of lactose and PRL binding, which increased linearly in a time-dependent manner thereafter. These results indicate that pregnant mice after 11 days are able to initiate synthesis of casein and lactose in parallel. Mammary glands were cultured with insulin, cortisol and PRL. The mammary explants of pregnant mice at 7 and 9 days showed active synthesis of casein after a lag period of 2 days, suggesting that the mammary gland in early pregnancy is less sensitive to PRL, probably due to the absence of an increase in PRL binding after ovariectomy.

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Rabbit mammary gland PRL receptors in the microsome fraction were solubilized with the zwitterionic detergent Chaps, and were separated into two fractions (Fr. A and B) by ion-exchange chromatography. The number of receptors in Fr. B was about 2.2 times greater than in Fr. A. In sucrose gradient centrifugation analysis, PRL receptors in Fr. A and Fr. B sedimented at different positions. After binding ¹²⁵I-PRL, the apparent molecular weight (mol wt) of the PRL receptor in Fr. A changed from 42, 400 to 65, 500 and that in Fr. B changed from 89, 400 to 108, 000, suggesting that each binding subunit interacts with one PRL molecule. Cross-linking ¹²⁵I-PRL to receptors revealed little change following SDS-PAGE, in the autoradiogram patterns of the microsome PRL receptors, either in the presence or absence of dithiothreitol. Both the microsome and the Chaps extract contained two major binding subunits (mol wt, 83, 200 and 36, 800) and one minor subunit (mol wt, 20, 800). The mol wt of the dominant PRL receptors in Fr. A and Fr. B were 36, 800 and 83, 200, respectively. The latter form did not dissociate into a 36, 800 mol wt form, suggesting that the rabbit mammary gland contains two independent binding subunits with mol wt of 36, 800 and 83, 200. Data showed that PRL receptors in the rabbit mammary gland are mostly the high Kd type receptor with a mol wt of 83, 200.

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Immature rabbits, guinea pigs and mice were injected with estradiol cyclopentylpropionate (ECP) or diethylstilbestrol (DES) for 3 days to evaluate whether estrogen enhances follicular maturation. Also, estrogen receptors in the ovary and uterus from these animals were measured. Uterine weight increased in all animals treated with ECP or DES, whereas actual ovarian weight increased only in the guinea pig. This correlated with the ability of estrogens to significantly increase the number of antral follicles in the guinea pig ovary. In the rabbit and mouse, estrogen increased only the number of small or large preantral follicles. However, the number of estrogen binding sites in the ovarian cytosol and nucleus was greater in the rabbit and the mouse than in the guinea pig. The affinity of ovarian cytosol receptors was the lowest for the guinea pig among the 3 species. Thus it is seen that estrogen does not enhance follicular maturation in all animal species. The ovarian response to estrogen is not only dependent upon estrogen receptors but also unknown mechanism (s) that may be related to paracrine or autocrine functions.

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We studied the interaction between synthetic atrial natriuretic peptide (ANP) and various vasoactive substances, which included isoproterenol (ISO), aminophylline (AMI), and dibutyryl cyclic AMP (dBcAMP) as vasodilators, and angiotensin II (AII) and norepinephrine (NE) as vasoconstrictors, and prazosin as an alpha-blocker in isolated perfused rat kidneys (IPK).
When 10^-9 mol of ANP was administered in 75 ml of a perfusate, the renal vascular resistance (RVR) was transiently decreased for 5 min, and increased thereafter. Simultaneously, ANP increased the glomerular filtration rate (GFR), urine flow (UV), absolute Na excretion (UNaV) and absolute K excretion (UKV).
All of the abovementioned effects of ANP were significantly inhibited by administering ISO, AMI or dBcAMP. On the other hand, the administration of AII and NE significantly enhanced the increases in UV and UNaV and the fractional excretion of Na induced by ANP, although AII and NE had no influence on the changes in RVR and GFR induced by ANP.
Prazosin did not modify the renal effects of ANP. These results suggest that the natriuretic effect of ANP is inhibited by agents that increase cyclic AMP in vascular smooth muscle cells. It is also suggested that the natriuretic effects of ANP can be explained by an increase in GFR and changes in intrarenal hemodynamics, rather than by the direct effect of ANP on renal tubules.

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The expression of renin and angiotensinogen genes in the human placenta and related tissues has been examined by RNA blot hybridization analysis with specific human complementary DNA (cDNA) probes. Renin mRNA was detectable in the chorion throughout pregnancy and in the hydatidiform moles, but not in the decidua, amnion or myometrium. The relative concentration of renin mRNA in the chorion was at the highest level in early pregnancy and decreased thereafter, while the total amount contained in the whole placenta was at the lowest level in early pregnancy, and increased thereafter, reaching at term about one-sixth of the total renin mRNA in the kidney. Hydatidiform moles had an even higher concentration of renin mRNA than the early chorion. There was no significant difference in either the relative concentration or the total renin mRNA content in the placentae from 4 normal and 4 toxemic pregnancies. Angiotensignogen mRNA was undetectable in any of the placental tissues, hydatidiform moles or myometrium. These results show that renin is synthesized in the placenta, possibly to play some physiological role locally by utilizing angiotensinogen which is abundantly present in the maternal systemic circulation.

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The opioid-binding activity of digitonin extract of bovine adrenal medullary membranes was studied.[³H] Diprenorphine binding to the solubilized material was rapid and saturable. The dissociation constant of [³H] diprenorphine binding was 0.76 nM. Several opioids displaced the [³H] diprenorphine binding. The complex of [³H] diprenorphine and the solubilized binding sites was eluted as a single peak on a Sepharose 6B column and showed an apparent molecular weight of 200, 000. These results indicate that active opioid receptors are solubilized with digitonin from bovine adrenal medullary membranes.

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The levels of immunoreactive, β-endorphin (ir-β-EP) were measured in the brain and pituitary of lean Zucker rats subjected to food deprivation for 72h and to a high fat diet, and in fatty Zucker rats after food deprivation for 72h. ir-β-EP was increased in the neurointermediate (NI-) pituitary lobe but reduced in the edulla-peons of fatty rats when compared to lean littermates fed ad libitum. Food deprivation decreased ir-β-EP in the cortex and medullapons of lean rats and in the cortex, midbrain and NI-pituitary of fatty rats. In contrast, ir-β-EP was increased in the anterior pituitary of lean rats and in the striatum of fatty rats after deprivation. The high fat diet produced a decrease in ir-β-EP in the cortex, midbrain and NI-pituitary with an increase in the striatum and hypothalamus of lean rats. These results suggest that the ir-β-EP concentration could be diffrentially affcted in different brain regions of Zucker rats by changes in the energy balance.

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The effect of uni-and bilateral cryptorchidism on testicular inhibin and testosterone secretion and their relationships to gonadotropins were studied in rats. Mature Wistar male rats weighing approximately 300 g were made either uni-or bilaterally cryptorchid. Testicular inhibin and testosterone content and plasma levels of LH and FSH were examined 2 weeks later. A similar remarkable decrease in testicular inhibin content was found in uni-and bilaterally cryptorchid testes. On the other hand, the testicular testosterone content was significantly decreased only in unilaterally cryptorchid testis with an inverse increase in the contralateral testis. Plasma testosterone levels were normal and plasma LH and FSH increased significantly in both of the cryptorchid groups. These results showed that cryptorchidism impairs both Sertoli and Leydig cell functions. While testosterone production was compensated by increased LH for 2 weeks, neither inhibin secretion nor storage changed in cryptorchid or contralateral testes during the same period.

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To investigate how various concentrations of serum prolactin (PRL) influence the priming effect of luteinizing hormone releasing hormone (LH-RH) on the pituitary gland, 24 women with various blood PRL concentrations received intravenous injections of 100μg of synthetic LH-RH twice at an interval of 60 minutes and their serum LH and follicle-stimulating hormone (FSH) were measured and analysed. In the follicular phase with a normal PRL concentration (PRL<20ng/ml, n=6), marked first peaks of the two hormones following the first LH-RH stimulation and enhanced second peaks after the second LH-RH administration were observed, indicating a typical priming effect of LH-RH on gonadotropins, though the second response of FSH was more moderate than that of LH. In hyperprolactinemia, in which the serum PRL concentration was higher than 70ng/ml (n=13), the basal concentration of gonadotropins was not significantly changed but the priming effect of LH-RH on LH and FSH was significantly decreased (p<0.01). No marked second peaks of LH and FSH were observed, suggesting an inhibitory effect of hyperprolactinemia on the second release of LH and FSH. In contrast, this effect was restored in a group of women whose serum PRL concentration was between 30 and 50ng/ml (n=5). Furthermore, enhanced second peaks of both LH and FSH were noted after successful bromocriptine therapy reduced hyperprolactinemia (PRL>70ng/ml) to less than 25ng/ml (n=5). Statistical analysis of the first and second peak ratio (Δ1Δ2 ratio) of LH and serum PRL concentration revealed that these two factors correlated well with each other (r=0.9500). These data suggest that the priming effect of LH-RH can be utilized for the evaluation of the pituitary function of secreting gonadotropin in hyperprolactinemia.

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Studies were carried out to investigate central actions of vasoactive intestinal polypeptide (VIP) and neurotensin (NT) on systemic blood pressure (BP), heart rate (HR) and salivary secretion in urethane-anesthetized male rats. Intraventricular (i. c. v.) administration of VIP caused dose-related increases in BP, HR and salivary secretion. Nearly maximum values were obtained at the dose of 2.0 μg for BP and 10.0 μg for salivary secretion, whereas the increase in HR did not attain the maximum even with the dose of 10.0 μg. Administration of hexamethonium (i. v.) completely blocked the increasing response of BP and HR, and the administration of pimozide (i. p.) or phenoxybenzamine (i. v.) reduced them. The increasing response of salivary secretion was almost completely blocked by all of the drugs.
The administration of NT (i. c. v.) produced no change in the BP, HR and salivary secretion.
The present results indicate that, 1) centrally administered VIP may somehow augment the sympathetic nerve discharge and/or adrenal medulla secretion, and 2) central VIP may play a role in the control of salivary regulation, nrobablv through sympathetic nerves.

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The responses of plasma glucose, insulin (IRI), glucagon (IRG) and free fatty acids (FFA) following alanine loading (0.1g/kg) were observed in 9 control subjects and 7 hyperthyroid patients, before and after restoration of thyroid function to normal. Despite the persistence of impaired glucose response to alanine, the blunted IRI and IRG responses in the hyperthyroid state were improved with a significant reduction in fasting IRI and IRG after treatment. Markedly increased FFA following alanine loading in hyperthyroid patients was reduced after treatment, but the FFA concentration remained greater than in the control subjects. We tentatively conclude that the impaired a and β-cell responses to alanine were temporarily induced by the direct and/or indirect effects of thyroid hormone excess.

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The effect of dexamethasone (Dex) on growth hormone (GH) release was examined in vitro in monolayer culture of normal rat pituitary cells and human somatotropinoma cells from patients with acromegaly. In either cell strain, Dex, at a concentration of 50 nM initially inhibited, but later (48≤h) potentiated, the release of GH into the medium, with or without growth hormone releasing hormone (GHRH). The intracellular GH was significantly increased by 4-hour incubation with Dex in rat cell cultures. These results indicate a biphasic effect of glucocorticoids on GH release, irrespective of the origin of somatotrophs, and that the initial inhibitory effect is probably caused by inhibition of the release.

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A case of thyroid papillary carcinoma associated with dyshormonogenetic goiter is reported. The patient, a 35-year-old male, had been on thyroid hormone therapy since the age of three because of familial dyshormonogenetic goiter. He developed a distinct tumor in the right lobe, which was suggestive of carcinoma upon physical as well as ultrasonographic examination. Total thyroidectomy was performed, since a frozen section disclosed a focus of papillary carcinoma and the possibility of future development of further malignancy in any remaining thyroid tissue was considered. The patient is currently well with complete thyroid hormone supplementation one and a half years after the operation.

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We have examined the activities of phospholipid/Ca²⁺-dependent and cyclic AMP-dependent protein kinases of the parathyroid adenomas and the atrophic glands which were resected from three patients with primary hyperparathyroidism. Phospholipid/Ca²⁺-dependent protein kinase activity of atrophic parathyroid gland was exclusively present in cytosol fraction (90.7±12.3%). On the other hand, phospholipid/Ca²⁺-dependent protein kinase activity of parathyroid adenomas was 66.9±6.4% in cytosol and 33.1±6.4% in membrane fraction, suggesting a translocation of the enzyme from the cytosol to the membranes. Cyclic AMP-dependent protein kinase activity appeared to be higher in parathyroid adenoma than in atrophic parathyroid gland in both cytosol and membrane fractions.

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