Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner

Study question: Does triiodothyronine (T3) regulate the secretion of angiogenic growth factors and cytokines by human decidual cells isolated from early pregnancy? Summary answer: T3 modulates the secretion of specific angiogenic growth factors and cytokines, with different regulatory patterns observed amongst various isolated subpopulations of human decidual cells and with a distinct change between the first and second trimesters of pregnancy. What is known already: Maternal thyroid dysfunction during early pregnancy is associated with complications of malplacentation including miscarriage and pre-eclampsia. T3 regulates the proliferation and apoptosis of fetal-derived trophoblasts, as well as promotes the invasive capability of extravillous trophoblasts (EVT). We hypothesize that T3 mayalso have a direct impact on human maternal-derived decidual cells, which are known to exert paracrine regulation upon trophoblast behaviour and vascular development at the uteroplacental interface. Study design, size, duration: This laboratory-based study used human decidua from first (8–11 weeks; n ¼ 18) and second (12–16 weeks; n ¼ 12) trimester surgical terminations of apparently uncomplicated pregnancies. Participants/materials, setting, methods: Primary cultures of total decidual cells, and immunomagnetic bead-isolated populations of stromal-enriched (CD10+) and stromal-depleted (CD102) cells, uterine natural killer cells (uNK cells; CD56+) and macrophages (CD14+) were assessed for thyroid hormone receptors and transporters by immunocytochemistry. Each cell population was treated with T3 (0, 1, 10, 100 nM) and assessments were made of cell viability (MTT assay) and angiogenic growth factor and cytokine secretion (immunomediated assay). The effect of decidual cell-conditioned media on EVT invasion through Matrigel was evaluated. Main results and the role of chance: Immunocytochemistry showed the expression of thyroid hormone transporters (MCT8, MCT10) and receptors (TRa1, TRb1) required for thyroid hormone-responsiveness in uNK cells and macrophages from the first trimester. The viability of total decidual cells and the different cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P , 0.05) and increased angiopoietin-2 secretion by stromal depleted cells (P , 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P , 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P , 0.05), and reduced granulocyte macrophage colony stimulating factor (P , 0.01), IL-8 (P , 0.05), IL-10 (P , 0.01), IL-1b (P , 0.05) and monocyte chemotactic protein -1 (P , 0.001) secretion by macrophages, but increased tumour necrosis factor-a secretion by stromal-depleted cells (P , 0.05) and increased IL-6 by uNK cells (P , 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P , 0.01) but did not affect cytokine secretion byuNKcells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro. Limitations, reasons for caution: Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo. Wider implications of the findings: Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory ‘switch’ in T3 responsiveness between the first and second trimesters, and support the notion that the timely and early correction of maternal thyroid dysfunction is critical in influencing pregnancy outcomes

A prospective controlled study of the impact of hyperthyroidism on reproductive function in males

The aim of this prospective controlled study was to ascertain the effect of hyperthyroidism on sperm quality and composition. We studied 23 thyrotoxic male patients, aged 43.8 ± 2.4 yr (mean ± SEM), and 15 healthy male controls of approximately the same age (42.2 ± 2.2 yr). Two semen analyses at intervals of 2-3 wk were obtained before and about 5 months after euthyroidism was achieved either by methimazole alone (14 patients) or 131I plus methimazole (9 patients). Total fructose, zinc (Zn), and magnesium (Mg) were also measured in seminal plasma in 16 patients, because 7 had semen volume less than 2 ml. In the control group semen analysis was performed only once. Mean (±SEM) semen volume was within normal range both in patients (3.3 ± 0.2 ml) and controls (3.5 ± 0.4 ml; P = NS). Mean sperm density was lower in patients, although the difference compared with controls did not reach statistical significance (35.7 ± 5.3 vs. 51.5 ± 6.1 × 106/ml; P = 0.062). The same was found with sperm morphology (68 ± 7% vs. 78 ± 8%; P = NS). Finally, mean motility was lower in thyrotoxic males than in controls (28 ± 8% vs. 57 ± 7%; P < 0.01). After treatment, sperm density and motility improved [35.7 ± 5.3 vs. 43.3 ± 6.5 × 106/ml (P = NS) and 28 ± 8% vs. 45 ± 7% (P < 0.05), respectively], but sperm morphology did not change (68 ± 7% vs. 70 ± 6%; P = NS). Mean values for fructose, Zn, and Mg did not differ between controls and patients either before or after achievement of euthyroidism [9.2 ± 0.7, 3.0 ± 0.5, and 4.2 ± 0.7 nmol/liter vs. 8.6 ± 0.9, 3.0 ± 0.5, and 4.7 ± 0.8 nmol/liter (patients before) and 9.1 ± 0.7, 3.1 ± 0.6, and 4.5 ± 0.9 nmol/liter (patients after treatment) for fructose, Zn, and Mg, respectively]. Moreover, according to the treatment given, no statistically significant differences were found before or after treatment. Finally, seminal plasma fructose, Zn, and Mg levels did not correlate with sperm parameters or with pretreatment thyroid hormone levels. In conclusion, the results of our study indicate that male patients with hyperthyroidism have abnormalities in seminal parameters, mainly sperm motility. These abnormalities improve or normalize when the patients become euthyroid. Restoration of sperm parameters was independent of the treatment provided for the hyperthyroid syndrome. Moreover, seminal plasma elements, such as fructose, Zn, and Mg, did not correlate with sperm density, motility, or morphology

Measuring disease activity to predict therapeutic outcome in Graves' ophthalmopathy

OBJECTIVE: The concept of disease activity in Graves' ophthalmopathy (GO) might explain why as many as one-third of patients do not respond to immunosuppressive treatment, because only patients in the active stage of disease are expected to respond. The hypothesis was adopted that a parameter used to measure disease activity should be able to predict a response to immunosuppressive treatment. The aim of this study was to develop a multivariate prediction model in which all previous tested activity parameters are integrated. DESIGN AND PATIENTS: We included 66 consecutive patients with untreated moderately severe GO who had been euthyroid for at least 2 months. All patients were treated with radiotherapy. Measurements Treatment efficacy after 6 months follow-up was used as the primary outcome measure. Disease severity and 15 different disease activity parameters were assessed before treatment. Univariate and multivariate logistic regression models were used to predict response (model 1) or no change (model 2). RESULTS: In multivariate analyses, we found that duration of GO, soft tissue involvement, elevation, soluble interleukin-2 receptor (sIL-2R), soluble CD30 (sCD30), eye muscle reflectivity and octreotide uptake ratio were significant predictors of a response to radiotherapy. Gender, duration of GO, soft tissue involvement, eye muscle reflectivity, IL-6 and urinary glycosaminoglycan (GAG) excretion were significant predictors of no change upon radiotherapy. Prognostic score charts were developed for use in clinical practice to calculate the probability of response (model 1) and the probability of no change (model 2) for each new patient. Finally we used a combination of both models to define a recommended treatment modality for each individual patient, based on both the predicted probabilities of response and no change. We were able to identify the correct treatment (based on a comparison with the observed response) in 89% of the patients. CONCLUSIONS: Although we strongly recommend that our results should be confirmed in other studies, our findings are the first evidence for the idea that disease (in)activity should determine which kind of treatment should be use