TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves' disease and Graves' ophthalmopathy.

PURPOSE: Intronic thyroid-stimulating hormone receptor polymorphisms have been associated with the risk for both Graves' disease and Graves' ophthalmopathy, but results have been inconsistent among different populations. We aimed to investigate the influence of thyroid-stimulating hormone receptor intronic polymorphisms in a large well-characterized population of GD patients. METHODS: We studied 279 Graves' disease patients (231 females and 48 males, 39.80 ± 11.69 years old), including 144 with Graves' ophthalmopathy, matched to 296 healthy control individuals. Thyroid-stimulating hormone receptor genotypes of rs179247 and rs12885526 were determined by Real Time PCR TaqMan(®) SNP Genotyping. RESULTS: A multivariate analysis showed that the inheritance of the thyroid-stimulating hormone receptor AA genotype for rs179247 increased the risk for Graves' disease (OR = 2.821; 95 % CI 1.595-4.990; p = 0.0004), whereas the thyroid-stimulating hormone receptor GG genotype for rs12885526 increased the risk for Graves' ophthalmopathy (OR = 2.940; 95 % CI 1.320-6.548; p = 0.0083). Individuals with Graves' ophthalmopathy also presented lower mean thyrotropin receptor antibodies levels (96.3 ± 143.9 U/L) than individuals without Graves' ophthalmopathy (98.3 ± 201.9 U/L). We did not find any association between the investigated polymorphisms and patients clinical features or outcome. CONCLUSION: We demonstrate that thyroid-stimulating hormone receptor intronic polymorphisms are associated with the susceptibility to Graves' disease and Graves' ophthalmopathy in the Brazilian population, but do not appear to influence the disease course.

Is diffuse and peritumoral lymphocyte infiltration in papillary thyroid cancer a marker of good prognosis?

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequently diagnosed endocrine neoplasia, representing 70 to 80% of all diagnosed thyroid cancers. Furthermore, Hashimoto's thyroiditis is a frequent inflammatory thyroid disease and the main cause of hypothyroidism. The relationship between Hashimoto's thyroiditis and PTC remains controversial. METHODS: Surgery for PTC was performed at our institution on 157 consecutive patients. They were classified by the degree of lymphocyte infiltration (LI). LI was classified as diffuse LI or peritumoral LI (only in or around the tumor), or absent. In addition, age, gender, tumor size, histopathological findings, lymph-node metastasis, extra- thyroidal extension, multifocal tumor, coexistence of LI and clinical outcomes were analyzed. RESULTS: Out of the 141 patients included in the study, 83 (59%) had diffuse LI and 22 (16%) had peritumoral LI. In 36 patients (25%) LI was absent. A comparison of patients in the 3 groups revealed no significant difference in their genders, ages, smoking status, thyroid function, or nodule size at the time of surgery. The characteristics of PTC showed no differences in lymph-node metastasis, tumor invasion into contiguous neck structures, angioinvasion, or PTC subtypes. Tumor-node-metastasis (TNM) classification and classes did not differ among the 3 groups. During the follow-up, 64 out of 141 patients with PTC (55%) had recurrences from 6 to 130 months after the initial treatment. After a mean follow-up period of 8 yr we observed a significantly (p=0.01) high recurrence (66.6%) in the LI absent group with 24 of 36 patients when compared to patients from the diffuse LI group (32 out of 83 patients; 38.5%) and peritumoral LI group (8 out of 22 patients; 25%). CONCLUSIONS: Although the role of the inflammatory-immune cells is complex and little understood, we found a more favorable course of PTC in the presence of LI (diffuse or peritumoral); this supports the hypothesis that LI represents a form of immune reaction to control tumor growth and proliferation.

Influence of methimazole and radioactive iodine treatment in the serum levels of the chemokine CXCL10 in hyperthyroid patients with Graves' disease.

The chemokine CXCL10 plays an important role in Graves' disease (GD); however, data regarding the effectiveness of therapy are contradictory. Serum CXCL10 levels in 31 hyperthyroid patients were measured before and after establishing euthyroidism: 16 newly diagnosed GD patients received methimazole (MMI), 15 relapsed GD patients were treated with radioactive iodine (RAI), and 18 healthy subjects served as a control group. Baseline serum CXCL10 levels were higher than in controls (MMI group 144.0 ± 48.24, RAI group 156.3 ± 71.81 and control 71.32 ± 26.03 pg/ml; p < 0.01). In the MMI group, serum CXCL10 levels decreased following euthyroidism at 6 months (76.51 ± 22.06 pg/ml; p < 0.01) and 12 (76.42 ± 34.07 pg/ml; p < 0.01). In the RAI group, serum CXCL10 levels decreased after 3, 6, 9, and 12 months of RAI administration (82.37 ± 55.01, 66.35 ± 48.62, 68.76 ± 28.87, and 74.94 ± 49.74 pg/ml, respectively; p < 0.05). Elevated serum TRAb levels in the MMI group (33.15 ± 30.84) decreased at 6 months (14.64 ± 16.57 IU/l; p = 0.0070), whereas in the RAI group (44.61 ± 60.66 IU/l) they increased to a peak level at 6 months (66.40 ± 104.2 IU/l; p = 0.003), which was significantly higher than those of the MMI group, but were decreased at 12 months (28.91 ± 35.13 IU/l). Serum CXCL10 levels correlated with FT3 (r = 0.48, p < 0.0001), FT4 (r = 0.47, p < 0.0001) and TRAb (r = 0.37, p = 0.0014). In conclusion, these data show a relationship between serum CXCL10 and GD activity and suggest that a more complex mechanism is involved in the generation of the thyroid auto-antibodies TPOAb and TRAb.

Association of circulating antibodies against double-stranded and single-stranded DNA with thyroid autoantibodies in Graves' disease and Hashimoto's thyroiditis patients.

The occurrence of antinuclear antibody (ANA), rheumatoid factor (RF), antibodies to double-stranded DNA (anti-dsDNA) and to single-stranded DNA (anti-ssDNA) was investigated in 51 patients with autoimmune thyroid diseases (AITD), and in 25 matched control subjects. In comparison with controls, the prevalence of anti-dsDNA was 74.5% in AITD patients (p=0.0001), 82.0% in 39 hyperthyroid Graves' disease (GD) (p=0.0001), and 50.0% in 12 euthyroid Hashimoto's thyroiditis (HT) patients (p=0.0001). The prevalence of anti-ssDNA was 90.1% in AITD (94.8% in GD and 75% in HT; p=0.001). The concentration of both anti-dsDNA and anti-ssDNA were higher (p=0.002) in AITD, in GD (p=0.001), and in HT (p=0.01) patients than in controls. Two patients with AITD were identified as positive for ANA. RF was detected in 4 AITD patients. Positive correlation was noted between anti-dsDNA with T4 (p=0.001), T3 (p=0.002), thyroid peroxidase antibody (anti-TPO) (p=0.0001), and TSH (p=0.001) values but not with thyroglobulin antibody (anti-Tg). Serum anti-ssDNA values were also correlated with T3 (p=0.0001), TSH (p=0.003), and anti-TPO (p=0.0001). However, by using a multiple regression analysis only anti-TPO remained associated with anti-dsDNA and both anti-Tg and anti-TPO with anti-ssDNA values. The predisposition to develop systemic autoimmune disorders is not influenced by thyroid hormones. The elevated prevalence of serum anti-dsDNA and anti-ssDNA in AITD patients points out that we must be aware of the risk for predisposition for the development of other systemic autoimmune diseases.

Análise crítica da terapêutica insulínica: dificuldades a serem resolvidas em diferentes níveis de atençäo à saúde / Critical analysis of insulinic therapy: dificulties to be solved in different health care levels

Após os animadores resultados do DCCT, a terapêutica insulínica intensiva tem sido recomendada indistintamente em todos os países. Em nossa experiência, aplicada à população de pacientes diabéticos em uso de insulina, atendidos no Hospital Universitário da PCCAMP, tal esquema se mostrou inviável e inadequado, a despeito de contarmos com o atendimento multiprofissional recomendado à assistência do paciente diabético. As razões socioeconômicas e culturais constituíram o principal fator limitante a esta prática. Devido a isto utilizamos em nosso serviço um esquema terapêutico adaptado, que denominamos "insulinização por etapas, através de doses duplas combinadas". Tal método foi o que mostrou melhores resultados devido à fácil inteligibilidade, e porque atribui responsabilidades ao paciente quanto aos resultados a serem obtidos. Desta forma, entre 50 pacientes em uso de insulina, obtivemos sessenta e quatro por cento de bom controle em um tempo médio de seguimento ambulatorial semanal que durou oito semanas. Os pacientes com mau controle glicêmico (trinta e sies por cento) foram reanalisados, caso, para correção das possíveis causas. A casuística final computou oitenta e seis por cento de bom controle glicêmico, sendo que em quatorze por cento dos casos este objetivo não foi alcançado. Entendemos, que algumas das causas de mau controle glicêmicosão de fácil detecção e podem ser corrigidos em nível primário de atenção à saúde. Entretanto, outras causas bastante complexas que dificultam o controle deverão ser referendadas aos setores secundários e terciário de atendimento, visando propiciar o controle glicêmico ótimo a todos os pacientes diabéticos

Case selection and restrictions recommended to patients with hyperthyroidism in South America.

Data from South America related to the use of radioiodine therapy indicate that radioiodine is prescribed only by physicians with special training and a license. A thyroid dose of 131I > 29 mCi requires hospitalization of the patient. Members of the Latin American Thyroid Society (LATS) (235 physicians) were surveyed by a questionnaire on their management of Graves' disease, and the survey procedure was the same used by the other thyroid societies. Thyroid uptake/scintigraphy was carried out by 60% of respondents and 131I was the isotope most used (chosen by 95% of respondents). Serum total T4 and T3 were requested by 97%, of LATS members whereas measurement of free T4 and TSH was employed less frequently (27% and 46.3%, respectively). The therapy of choice for 83% of responding members was antithyroid drugs. Radioiodine was chosen by 15.3% of respondents. For most respondents, the aim of 131I therapy was to restore euthyroidism. It was based on goiter size and thyroid uptake and administered in a single dose. For the radioiodine therapy, 55.5% of the respondents did not add any other medical treatment. The remaining group used antithyroid drugs before 131I (50%), and 77% employed it after the dose. There is a general consensus to provide the 131I treatment only to patients > 18 years of age. 131I was overwhelmingly (64.2% versus 34% of drug therapy) the therapy seen as most appropriate for patients with recurrence or old age. The predominant use of antithyroid drugs for therapy of Graves' disease in South America was similar to that in Europe and Japan but different from the practice in North America.

Effect of L-thyroxine administration on antithyroid antibody levels, lipid profile, and thyroid volume in patients with Hashimoto's thyroiditis.

The changes in the serum thyroid autoantibodies, antithyroglobulin (TgAb) and antithyroid-peroxidase (TPOAb), lipid profile, and thyroid volume following L-thyroxine (L-T4) therapy is still a controversial matter. We studied 23 patients with goiter due to Hashimoto's thyroiditis; 10 had clinical hypothyroidism (CH) and 13 had subclinical hypothyroidism (SH). Both groups received L-T4 (2.0 to 2.5 micrograms/kg/day) for a median period of 6 months. Serum concentration of TgAb (normal value: < 200 mUI/mL) and TPOAb (normal value: < 150 mUI/mL) were measured by a sensitive IRMA using 125I protein-A. Thyroid volume was determined by ultrasound (normal value: 8-14 mL). At the end of the observation period the median serum TSH concentration decreased significantly in both groups (42.9 to 0.55 in CH and 2.4 to 0.74 mU/L in SH patients) and serum FT4I levels increased only in the CH group (0.87 to 2.1; p < 0.05). Serum TgAb concentration did not change in SH patients (72 to 218 mUI/mL) but declined in CH patients (364.5 to 75 mU/mL; p < 0.05). TPOAb levels also fell in the CH group (871 to 194 mUI/mL; p < 0.05) and no significant change was noted in SH patients (260 to 116 mUI/mL). Further, a significant correlation was obtained between TSH and either TPOAb concentration (rs = 0.569, p < 0.01) or thyroid volume (rs = 0.488, p < 0.05) in the CH group but not in SH patients (rs = 0.232, NS). LDL-cholesterol was higher in the CH (159.4 mg/dL) compared with the SH group (116 mg/dL). Moreover, only in the CH patients was there a significant fall in total cholesterol (224.5 to 165.5 mg/dL, p < 0.05) and in LDL-cholesterol (159.4 to 104.3 mg/dL, p < 0.05) values. The thyroid volume decreased in all patients with CH and in 77% (10/13) of SH patients and a significant median in the thyroid volume decrease was found (39.7% of initial volume in the CH group and 80.9% in SH patients; p < 0.01). The influence of L-T4 on both thyroid autoantibody levels and thyroid volume might be explained by reduction of antigenic substance through a decreased stimulation of thyroid tissue by circulating TSH as was seen in CH but not in SH patients. The benefits of the administration of L-T4 replacement therapy in SH patients due to Hashimoto's thyroiditis remain to be clarified.

Metabolism of glucose and glutamine in lymphocytes from Graves' hyperthyroid patients: influence of methimazole treatment.

Several studies have shown that thyroid hormones are able to influence selected immune responses such as cell mediated immunity, differentiation of B lymphocytes and the activity of NK cells. These hormones can also regulate the metabolism of glucose and glutamine in rat macrophages and their effects seem to occur mainly through the Krebs cycle. Alterations in the hexokinase, citrate synthase, glucose-6-phosphate dehydrogenase and glutaminase activities in lymphocytes from patients with Graves' disease, either untreated or on methimazole (MMI) therapy were investigated. Experiments were also done in vitro to determine the activities of these enzymes in normal lymphocytes cultured for 24 h in the presence of MMI T3 and T4 using concentrations close to the physiological. Changes in the conversion of [U-14C]-glucose and [U-14C]-glutamine to 14CO2 as caused by the addition of MMI, T3 or T4 to the culture medium were also evaluated. The results indicate that high levels of thyroid hormones might stimulate the metabolism of glucose and glutamine for a short period of time but, if the stimulus is maintained, the utilization of glutamine by lymphocytes is then suppressed. Moreover, MMI does affect lymphocyte metabolism but the significance of this finding for its immunosuppressive effect remains to be examined.

Elevation of cord blood TSH concentration in newborn infants of mothers exposed to acute povidone iodine during delivery.

The thyroid function in full term newborn infants of 30 pregnant women given topical germicide providine-iodine (PVPI) during delivery was evaluated. For comparison 12 full term newborn infants of pregnant women using clorhexidine hydrochloride as germicide in selective cesarean section were designed as control. The two pregnant groups had similar median age (27.5 yr in PVPI group, range: 19-42 yr and 28.5 yr in control group, 19-40 yr) and gestational age (39 weeks, 38-42 weeks and 39.5 weeks, 38-42 weeks). Birth weight (3365 g, 2500-3860 g and 3265 g, 2850-4000 g) and the apgar score (9, 9-10 and 9, 8-10) of newborn were similar in both groups. Umbilical cord blood samples were taken after immediate clamping and serum total T3, total T4, free T4 and TSH concentrations were assayed by an immunofluorimetric method. T3, T4 and free T4 concentrations in the cord blood were not different in PVPI newborn infants (median values: 0.92 nmol/L, 135 nmol/L, and 15.9 pmol/L), in comparison to control newborns (0.97 mmol/L, 140.9 nmol/L and 17.3 pmol/L). In contrast, cord blood TSH concentration in newborn infants of PVPI pregnant women (median value: 6.47 mIU/L) was significantly higher (p < 0.01) than in control newborn infants (4.8 mIU/L). In PVPI exposed group 14 out of 30 newborn infants had TSH concentration above the upper value (6.7 mIU/L) observed in the control groups (X2 = 8.4, p < 0.01). These data suggest that fetal thyroid is susceptible even to acute iodine overload and support the recommendation that PVPI should be avoided during pregnancy.

The evolution of Graves' ophthalmopathy during treatment with antithyroid drug alone and combined with triiodothyronine.

We analyzed the evolution of the ophthalmopathy associated with Graves' hyperthyroidism in 45 patients treated with two different antithyroid drug regimens. Group A patients (n = 31) received either methimazole (40-100 mg daily) or propylthiouracil (400-900 mg daily) combined with T3 daily throughout treatment. Group B patients (n = 14) were treated with conventional regimen with lower doses of either methimazole (5-25 mg daily) or propylthiouracil (50-300 mg daily) and no T3 addition. Eye signs and proptosis measurement were evaluated just before the beginning of the treatment and compared with the results after antithyroid drug withdrawal. Improvement of the eye signs considered on grounds of the NOSPECS classification was greater in group A than group B (p less than 0.01). Also, the decrease in proptosis measurement was greater (p less than 0.01) in patients treated with combined regimen (21.5 +/- 2.4 mm to 20.4 +/- 2.3 mm) than in patients receiving conventional therapy (20.4 +/- 1.6 mm to 20.0 +/- 1.7 mm). Serum thyroglobulin concentrations did not correlate with either the severity or the evolution of the ophthalmopathy. Negative serum antithyroglobulin antibody (TgAb) was associated with the improvement of the ophthalmopathy that was noted in 24 out of 27 patients (Chi-Square = 5.84; p less than 0.001). Thus, serum TgAb levels might have some connection with progression of eye signs but serum Tg concentration does not. Our study suggests that in most patients the transition from hyperthyroidism to euthyroidism induced by antithyroid drug therapy is associated with the improvement of the Graves' ophthalmopathy. However, no marked difference can be drawn between the two treatment regimens.

Androgenic expression in the submandibular gland of zinc-deficient mice.

The effects of zinc deficiency were studied in mice submandibular salivary glands (SMG). Zn-restricted mice (Zn-) were maintained from weaning until adult age (60 days) with a powdered diet containing 3 mg Zn2+/kg. Pair-fed animals (30 mg Zn2+/kg powdered diet) and control animals fed a regular pelleted diet were also used. Total protein content and proteolytic activity of SMG did not differ among the groups, but morphometric evaluations revealed significant alterations in the nucleus/cytoplasm size ratios, most likely due to an absolute reduction in nuclear volume (control = 122.5 +/- 6.4; Zn- = 91.6 +/- 10.5; pair-fed = 125.1 +/- 6.8 microns 3) paralleled by an increase of the height of the duct epithelium (control = 70.5 +/- 3.0; Zn- = 90.5 +/- 4.2; pair-fed = 81.7 +/- 3.0 microns). The altered food consistency could be responsible for these morphological changes. In order to assess the subcellular distribution of SMG androgen receptors in conditions of chronic Zn deficiency, Zn- animals were mated and the F1 generation was fed as their dams until the age of 45 days. Cytosolic (in 105,000 g supernatants) and nuclear (KCl-extracted) SMG receptors were determined with [3H]R1881. The Zn- animals had reduced nuclear/cytosolic ratios of androgen receptors (control = 0.62; Zn- = 0.14), as an indication that chronically deficient Zn intake determines a sort of destabilization of the interactions of androgen-receptor complexes with target cell nucleus.

[Comparative multicenter study of bovine insulin with forms more purified of swine and human insulin in the treatment of type 1 diabetes mellitus]. / Estudo multicêntrico comparativo da insulina bovina com formas mais purificadas de insulina suína e humana no tratamento de diabéticos do tipo I.

A multicentric double-blind randomized study was organized to investigate the relationship between insulin antibodies and metabolic control in type I diabetics who changed from bovine insulin to monopic porcine and monocomponent human insulin. Twenty eight type I diabetic patients treated with bovine insulin (proinsulin less than 3,000 ppm) were selected. In a 6 month study, 9 patients maintained bovine insulin, 9 changed to monopic porcine insulin (proinsulin less than 10 ppm) and 10 to human insulin (proinsulin less than 1 ppm). The insulin were a gift from Biobras laboratory. The insulin antibodies (IA) were measured by an ELISA method and the metabolic control assessed by fasting blood sugar (FBS), 24 hour glucosuria and glycated protein (GP) measured by affinity chromatography method. After switching insulin therapy, IA decreased with porcine and human insulin, but increased with bovine insulin. Concerning metabolic control, only an increase of FBS with human insulin was found. In the beginning of study, there was negative correlation between IA and 24h glucosuria (rs = -0.509; p = 0.006). In conclusion, there was no improvement of metabolic control, in spite of a decrease of IA in type I diabetics treated during 6 months with less immunogenic insulin preparations.

Serum thyroid-stimulating antibody, thyroglobulin levels, and thyroid suppressibility measurement as predictors of the outcome of combined methimazole and triiodothyronine therapy in Graves' disease.

The value of the criteria used to anticipate the outcome of treatment of Graves' hyperthyroid patients with methimazole (MMI) remains controversial. We have reported that high MMI doses combined with T3 administration was correlated with higher remission rates. In this study, we used the lowest MMI dose able to control the hyperthyroidism, keeping the free T4 index (FT4I) values below the normal range throughout treatment, and compared the results with patients treated with a high MMI regimen. Both groups received T3. We also evaluated the usefulness of goiter size, serum thyroid-stimulating antibody (TSAb: adenylate cyclase stimulation in human thyroid membrane), thyroglobulin (Tg) levels, and the T3 suppressibility of 24 h RAIU as prognostic markers for the outcome of Graves' disease therapy. Twenty-four Graves' hyperthyroid patients were treated with high MMI dose (mean +/- SD 60 +/- 19, range 40-120 mg daily), and 25 patients received low MMI dose (17 +/- 4.3, 5-20 mg daily). T3, 75 micrograms daily, was given to both groups of patients for 15 +/- 4 (13-22) months of treatment. After cessation of drug therapy, 31 patients (63%) remained euthyroid for 18 +/- 3 (13-49) months of follow-up, 15 (62.5%) and 16 (64%) patients in the high and low dose groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse effects related to thionamide drugs and their dose regimen.

The authors studied 389 Graves' hyperthyroid patients receiving either high propylthiouracil (PTU) or methimazole (MMI) daily doses or low doses to evaluate whether adverse effects were related to the thionamide drugs or its daily dose regimen. Group 1 patients (n = 286) received high PTU (728 +/- 216 mg/day, n = 92) or MMI (60 +/- 19 mg/day, n = 94) doses, and group 2 patients (n = 103) were treated with low PTU (255 +/- 85 mg/day, n = 39) or MMI (23 +/- 10 mg/day, n = 64) doses. Major adverse effects were observed in 11 (2.8%) patients. Of these, four (1.0%) had agranulocytosis, two (0.5%) were granulocytopenic and five (1.3%) had hepatotoxicity. Agranulocytosis occurred in two patients from each group, 0.7% and 1.9%, respectively from group 1 and group 2. There was no significant difference between the groups or the types of thionamide. There also was no correlation with the patients' age. All of the patients were hyperthyroid, and its onset occurred in the first to third month of treatment. Full recovery was achieved in all cases after drug withdrawal. Four of 5 patients with hepatotoxicity were treated with high PTU doses, and one patient received low MMI doses (p less than .05). All patients were euthyroid. Arthralgias, skin rash and gastric intolerance, the minor adverse effects of thionamides studied, were observed in 52 (13.4%) of the patients. Although no significant differences were found, most of the patients experiencing side effects were from group 1 an received MMI therapy. These adverse effects did not demand drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

"In vitro" study on release of cyclic AMP and thyroid hormone in autonomously functioning thyroid nodules.

The TSH effect on slice and the incubation medium cyclic AMP levels and T3 and T4 released from 8 autonomously functioning thyroid nodules (AFTN) and their respective perinodular (PN) tissues were examined. The thyroid slices were incubated in Eagle's Medium containing TSH (5 to 100 mU/ml) for 60 min and 300 min for tissue cyclic AMP generation and for cyclic AMP, T3 and T4 release, respectively. Basal cyclic AMP levels were not different either in AFTN and in PN slices or into the incubation medium. In both tissues TSH produced a similar cyclic AMP generation. In contrast, cyclic AMP released into the incubation medium was significantly higher in AFTN than in PN tissues, after TSH stimulation. Basal T3 values and TSH-stimulated T3 release in AFTN were not different from PN tissue. However, basal T4 levels were significantly higher in AFTN than in PN tissue as well as T4 released in response to TSH. In addition, T3/T4 ratio was lower in AFTN than in PN tissues. The cyclic AMP released into the incubation medium correlated with both T3 and T4 release in PN tissue but in the AFTN tissue no correlations were found. These findings suggest that the adenylate cyclase-cyclic AMP system is more sensitive to TSH-stimulation in AFTN when compared with PN tissue and that AFTN tissue has a preferential T4 secretion.

Thyroidal modulation of androgenic expression in mice submandibular gland.

We investigated the influence of testes and thyroid gland on the maintenance of biochemical parameters and of [3H]R1881 binding sites of adult mice submandibular gland (SMG). Castration (Cx) performed at beginning of puberty prevented sex-dependent SMG development without interfering with maximal androgen binding capacity. Thyroidectomy (Tx) had strong effects on SMG, mainly by lowering the number of androgen binding sites. All alterations could be fully reverted after treatment with testosterone (5 mg/animal, single dose) or with thyroxine (T4, 250 micrograms/animal per day during 5 days). The effects of Cx on SMG could be reverted by therapy with testosterone, T4, or with both hormones (testosterone + T4) in a non-synergistic fashion. It is shown the importance of thyroidal activity on the physiological maintenance of androgen receptors in the murine SMG; the role played by thyroid gland seems to be essential for the full expression of the androgen-dependent SMG activity in adult mice.

Ontogenesis of androgen receptors in the mouse submandibular gland: correlation with the developmental profiles of circulating thyroid and testicular hormones.

Specific binding of the synthetic androgen, [17 alpha-methyl-3H]methyltrienolone, to the cytosol fraction of the submandibular salivary gland (SMG) of male mice was studied in relation to the developmental profiles of testosterone and thyroid hormones in blood. The peak rise of serum triiodothyronine (T3) at prepubertal age was closely related to both the increase of maximal androgen-binding capacity in SMG and the conspicuous surge of proliferative activity as indicated by increased rate of glandular DNA content. Also, 2-month thyroidectomized mice had an age-related, strong reduction in the number of androgen-binding sites. On the other hand, the development of the secretory functions of the gland could be better related to the rise of circulating testosterone by days 25-30 of age. The results suggest that thyroid hormones play a very important role in the early induction and further maintenance of androgen receptors in the murine SMG.