Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells.

Ovarian granulosa cells synthesize estrogens from androgens, which are catalyzed by aromatase cytochrome P450 (P450arom). Troglitazone (Tro), one of the insulin-sensitizing compounds, thiazolidinediones (TZDs), is a ligand for peroxisome proliferator activated receptor gamma (PPARgamma) and is effective in the treatment of both non-insulin-dependent diabetes mellitus (NIDDM) as well as polycystic ovary syndrome (PCOS). PPARgamma exerts a transcriptional activity as a PPARgamma:RXR heterodimer. In this study, we investigated the effects of Tro and/or RXR ligand, LG100268 (LG) on the aromatase activity in cultured human ovarian granulosa cells obtained from patients who underwent in vitro fertilization. Human ovarian granulosa cells expressed PPARgamma mRNA assessed by RT-PCR. The treatment of the granulosa cells with Tro for 24 h resulted in a dramatic inhibition of the aromatase activity in a dose-dependent manner. While the treatment with LG alone also inhibited the aromatase activity, the combined treatment with both Tro and LG caused a much more reduction in the aromatase activity. The changes in the aromatase activity by Tro and/or LG were associated with comparable changes in P450arom mRNA assessed by RT-PCR. These results suggest that Tro directly inhibit the aromatase activity in human granulosa cells probably via nuclear receptor system PPARgamma:RXR heterodimer. The findings may provide a biochemical basis for the decrease in the blood concentrations of estrogens which is observed after the in vivo administration of Tro and may also possibly be useful as a novel therapy for estrogen-dependent diseases.

Congenital cytomegalovirus infection associated with fetal ascites and intrahepatic calcifications.

A fetus at 20 weeks' gestation was shown by ultrasonography to have ascites and intrahepatic calcifications. We aspirated the fetal ascites at 29 and 30 weeks' gestation to decompress the fetal lungs due to the progression of the ascites and the concomitant compression in the fetal lungs. The newborn had neither hypoplasia of the lungs nor any respiratory complication, though congenital cytomegalovirus infection was present. This is the first report of such congenital cytomegalovirus infection associated with fetal ascites and intrahepatic calcifications. Careful monitoring and early intervention is necessary for a good prognosis.

Histocompatibility lymphocytic antigen (HLA) typing in patients with acute exacerbation of Hashimoto's thyroiditis.

Histocompatibility lymphocytic antigen (HLA) typing was performed in 6 patients with acute exacerbation of Hashimoto's thyroiditis whose diagnoses were established on the basis of typical histological findings, and was compared with those of 12 with subacute thyroiditis, 33 with general Hashimoto's thyroiditis and also with a control group. There was a high incidence of BW35 in patients with subacute thyroiditis, although it was only seen in 1 of 6 patients with acute exacerbation. The difference was statistically significant (p less than 0.01). Four of 6 patients with acute exacerbation had DR2 and none of them had DR4, which was the reverse of the findings for Hashimoto's thyroiditis patients in general, and the difference in the incidence of DR2 was significant (p less than 0.001). None of the HLA types in patients with acute exacerbation was significantly different from those of the control group. In conclusion, HLA typing in patients with acute exacerbation was different from those of subacute thyroiditis and general Hashimoto's thyroiditis. Acute exacerbation was considered to involve quite a limited and rather unique population among patients with Hashimoto's thyroiditis.

Histological, clinical and laboratory findings of acute exacerbation of Hashimoto's thyroiditis--comparison with those of subacute granulomatous thyroiditis.

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.

Pathological characteristics of acute exacerbation of Hashimoto's thyroiditis--serial changes in a patient with repeated episodes.

A 76-year-old female patient with known Hashimoto's thyroiditis had 12 episodes of acute exacerbation, characterized by high fever and spontaneous pain in the thyroid over a period of 4 months. Percutaneous needle biopsies were performed before and serially after local steroid injection. Histological examination of the thyroid tissue involved obtained before steroid administration revealed quite a unique localized edematous and inflammatory appearance with rich but loosely arranged collagen fibers, and destruction of follicular structures and swollen degenerated epithelia. Neither remarkable cellular infiltrations nor granulomatous changes were observed in the area involved. Ultrasonogram showed an extremely hypoechoic lesion coincident with the location of pain and tenderness. Intrathyroidal administration of triamcinolone acetate (40 mg) resulted in an immediate relief of pain, fever and localized swelling. Surprisingly, remarkable histological improvements were observed even on the day following the injection. However, clinical manifestations as well as histological changes were reversed again within one week or so. After various therapeutic means, total thyroidectomy was performed which induced disappearance of the manifestations. The etiology remains unclear, but pathological findings observed in this patient may provide an insight into the pathogenesis of this rare but intractable condition.

Evaluation of radionuclide imaging and echography in the diagnosis of thyroid nodules.

Radionuclide imaging with both Tc-99m sodium pertechnetate and Tl-201 chloride was studied in 152 patients with thyroid nodules. Ultrasonography also was performed in 81 of those patients. Tc-99m sodium pertechnetate scans demonstrated nodules in 69.7% of 78 differentiated thyroid carcinomas (DC) and 72.2% of 54 thyroid adenomas (Ad). Tl-201 chloride was accumulated in 73.7% of DC and 53.6% of Ad. By combining the Tc-99m sodium pertechnetate and Tl-201 chloride scans, the detectability of the nodules was increased to 90.8% for DC and 88.9% for Ad, respectively. The Tc-99m sodium pertechnetate scans showed better visualization of cystic lesions than did the Tl-201 chloride imaging. The Tl-201 chloride images clearly demonstrated intrathoracic tumor invasions in six cases of carcinoma and two cases of Ad. The Tl-201 chloride scan was also of value in detecting regional lymph node involvement and the recurrence and metastasis after thyroidectomy. The detectability of space-occupying lesions by ultrasonography was 96.3% in 81 patients with thyroid nodules. Ultrasonography differentiated well between solid and cystic lesions. The presence and extent of nodular lesions were detected with radionuclide imaging and ultrasonography in 98.8% of patients. Radionuclide imaging combined with ultrasonography provides a rapid, convenient, and useful method for the localization and visualization of thyroid tumors.

Effect of bromocriptine on serum TSH in euthyroid patients with endocrine disorders.

In 10 euthyroid subjects a single 2.5 mg per os dose of bromocriptine caused rapid and remarkable decreases in serum TSH. As much as a 0.85 +/- 0.18 (s.d.) microU/ml decrease from the basal level (56 +/- 9%) was observed at 5 hours. A good correlation was observed between the basal TSH level and the TSH decrease after bromocriptine (r = 0.786). In 4 patients taking 5 to 15 mg bromocriptine daily (chronic administration group), another 2.5 mg bromocriptine also caused significant decreases in serum TSH, but the degree (0.42 +/- 0.03 microU/ml, 43 +/- 26% of basal) and duration (maximal at 4 hours) were less than those observed in the untreated group. The lowest TSH levels in these two groups did not differ significantly (0.80 +/- 0.45 and 0.78 +/- 0.53 microU/ml, respectively). The TSH decrease after bromocriptine in the untreated group was found not to correlate significantly with TRH induced TSH increase (r = 0.300). TRH induced TSH increase in the chronic administration group was similar to or greater than that of control subjects with matched basal TSH. The TSH lowering effects of per os prednisolone and triiodothyronine were also studied. Prednisolone exerted a quite similar effect to bromocriptine, but a certain time lag was observed in the case of triiodothyronine. A single dose of bromocriptine was found to lower serum TSH levels even in euthyroid subjects. The effect was considered to be independent of TRH-TSH regulation and to act directly on the TSH release.

Prognostic value of estrogen and prolactin receptor analysis in human breast cancer.

Hormone receptors for estrogen (ER), progesterone (PGR) and prolactin (PRL-R) were measured in primary breast cancer tissues obtained from 214 patients at radical mastectomy. The patients were followed up at intervals of one to three months to examine the relationship between hormone receptor status and prognosis. ER status was related to PGR status but not to PRL-R status. PRL-R was more frequently detectable in pathologic stage 3 than in stage 1 & 2 (22% vs. 10%, P less than 0.05) whereas ER and PGR were not different between stage 1 & 2 and stage 3 groups. The influence of receptor status on prognosis was analyzed in 164 patients of stage 1 & 2 by means of the actuarial life table technique. The recurrence-free interval was not related to ER, PGR or PRL-R status. The ER-positive group was associated with significantly prolonged survival compared with that of ER-negative patients at 42 to 51 months after surgery. PRL-R positive patients had a significantly worse survival than the PRL-R negative group (P less than 0.05). These findings indicate that receptor status may provide useful prognostic information in patients with early breast cancer and that the lactogenic hormone may play an unfavorable role in relation to the prognosis of human breast cancer.

A predicted case with neonatal transient hypothyroidism due to blocking type thyrotropin binding inhibitor immunoglobulins (TBII).

A 26-yr-old female with primary hypothyroidism due to potent blocking type thyrotropin binding inhibitor immunoglobulins (TBII) was advised of the high risk of bearing a baby with neonatal transient hypothyroidism. This prediction proved valid and her baby was found to be hypothyroid with a potent TBII. By expressing the baby's TBII as the absolute concentration, we found an almost linear regression of TBII and the half-life was calculated as 18.0 days. The TBII became undetectable by the 6th month and thyroid medication was stopped, however the baby remained euthyroid with subsequent normal physical and mental development.

Interrelation between somatostatin output from the mediobasal hypothalamus and plasma growth hormone levels in conscious rats: effects of glucagon administration.

The interrelationship between SRIF output from the mediobasal hypothalamus and plasma GH levels was studied in conscious male rats using the push-pull perfusion technique in combination with repeated blood samplings. The MBH was perfused with artificial cerebrospinal fluid at the rate of 30 microliter/min, and blood samples were collected every 20 min from 1000-1700 h. In control animals, which received injection of acidified saline at 1100 h into the lateral ventricle, two large episodes of spontaneous GH secretion occurred regularly at around 1200 and 1540 h, and troughs occurred around 1400 h. In contrast, SRIF levels from mediobasal hypothalamus perfusate fluctuated at random, ranging from 10-116 pg/ml, with a mean value of 39.2 pg/ml. Mean SRIF levels at 1200 and 1540 h (43.4 +/- 9.0 and 24.4 +/- 4.2 pg/ml, respectively; n = 8) were not different from those at 1400 h (39.9 +/- 12.2 pg/ml). When glucagon (10 micrograms/rat) was injected at 1100 h, plasma GH levels decreased and remained low until 1600 h, whereas perfusate SRIF levels were elevated and remained high for the period. In these animals, the mean plasma GH levels during 1120-1540 h were lower than those in control rats [17.2 +/- 2.4 ng/ml (n = 9) vs. 143.4 +/- 17.5 ng/ml (n = 8); P less than 0.01]. In contrast, the mean SRIF levels in glucagon-treated rats were higher than those in controls [112.5 +/- 15.9 pg/ml (n = 9) vs. control 40.1 +/- 4.3 pg/ml (n = 8); P less than 0.01]. These results suggest that SRIF plays a role in tonic inhibition of GH release in response to the intracerebroventricular injection of glucagon in conscious rats, although SRIF plays, if any, a minor role in regulating episodic GH secretion.

Effects of bromocriptine and tamoxifen on growth and hormone receptor levels of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats.

The role of prolactin (PRL) and estrogen in the growth of 7,12-dimethylbenz(a)-anthracene (DMBA)-induced rat mammary tumors was investigated. Tumor growth was suppressed by both bromocriptine and tamoxifen. Combined administration of ovine PRL and tamoxifen attenuated the inhibitory action of tamoxifen on tumor growth. Serum PRL levels were decreased by both bromocriptine and tamoxifen administration. Estrogen receptors (ER) in tumor tissues were decreased in number by tamoxifen, but not by bromocriptine. Progesterone receptors (PgR) in DMBA-induced mammary tumors were abolished by tamoxifen and significantly reduced by bromocriptine. Combined administration of ovine PRL with tamoxifen attenuated the inhibition of PgR induced by tamoxifen alone, while ER remained undetectable. Specific PRL binding to the liver was significantly reduced by treatment with bromocriptine, tamoxifen and tamoxifen plus ovine PRL, whereas PRL receptors in mammary tumor were not influenced by these drugs. These results suggest that PRL may stimulate DMBA-induced tumor growth independently of ER and that a part of the inhibiting effect of tamoxifen on tumor growth may be explained by the decreased PRL secretion.

Effects of tamoxifen on estrogen and progesterone receptors in human breast cancer.

Twenty patients with primary breast cancer were treated with tamoxifen (10 mg p.o. twice a day) for 1 to 4 weeks. Before and after the tamoxifen administration, tumor specimens were obtained and assayed for estrogen receptors and progesterone receptors (PGR). Total cytosol estrogen receptor (ERC) and occupied nuclear estrogen receptor (ERN) were measured by hydroxylapatite assay, and unoccupied PGR was measured by the dextran-coated charcoal assay. ERC, ERN, and PGR were detectable in 11, 8, and 6 tumors, respectively, before tamoxifen administration. After tamoxifen treatment, ERC decreased in 10 of 11 ERC-positive tumors. Occupied ERN increased in three of five ERN-positive tumors treated with tamoxifen for a short period (1 to 2 weeks), but they decreased in all of three ERN-positive tumors after longer administration (3 to 4 weeks). PGR increased in three of five ERN-positive tumors after short-term tamoxifen treatment, but they decreased in all of three tumors treated by the drug for a longer period. Increased PGR responses were accompanied by an increase of ERN in two of three ERN-positive tumors. These results suggest that tamoxifen interacts with the estrogen receptor system in human breast cancer tissue and may be estrogenic during short treatment, while longer treatment results in an antiestrogenic response.