Thyroid hormone is a critical regulator of growth, development, and metabolism in virtually all tissues, and altered thyroid status affects many organs and systems. Although for many years testis has been regarded as a thyroid hormone unresponsive organ, it is now evident that thyroid hormone plays an important role in testicular development and function. A considerable amount of data show that thyroid hormone influences steroidogenesis as well as spermatogenesis. The involvement of tri-iodothyronine (T₃) in the control of Sertoli cell proliferation and functional maturation is widely accepted, as well as its role in postnatal Leydig cell differentiation and steroidogenesis. The presence of thyroid hormone receptors in testicular cells throughout development and in adulthood implies that T₃ may act directly on these cells to bring about its effects. Several recent studies have employed different methodologies and techniques in an attempt to understand the mechanisms underlying thyroid hormone effects on testicular cells. The current review aims at presenting an updated picture of the recent advances made regarding the role of thyroid hormones in male gonadal function.

Imbalances in redox status modulate type 3 deiodinase induction in nonthyroidal illness syndrome. However, the underlying mechanisms that lead to D3 dysfunction under redox imbalance are still poorly understood. Here we evaluated D3 induction, redox homeostasis, and their interrelationships in the liver, muscle, and brain in an animal model of NTIS. Male Wistar rats were subjected to left anterior coronary artery occlusion and randomly separated into two groups and treated or not (placebo) with the antioxidant N-acetylcysteine. Sham animals were used as controls. Animals were killed 10 or 28 days post-MI induction and tissues were immediately frozen for biochemical analysis. D3 activity, protein oxidation and antioxidant defenses were measured in liver, muscle, and brain. Compared to those of the sham group, the levels of D3 expression and activity were increased in the liver (P = 0.002), muscle (P = 0.03) and brain (P = 0.01) in the placebo group. All tissues from the placebo animals showed increased carbonyl groups (P < 0.001) and diminished sulfhydryl levels (P < 0.001). Glutathione levels were decreased and glutathione disulfide levels were augmented in all examined tissues. The liver and muscle showed augmented levels of glutathione peroxidase, glutathione reductase and thioredoxin reductase activity (P = 0.001). NAC prevented all the alterations described previously. D3 dysfunction in all tissues correlates with post-MI-induced protein oxidative damage and altered antioxidant defenses. NAC treatment prevents D3 dysfunction, indicating that reversible redox-related remote D3 activation explains, at least in part, the thyroid hormone derangements of NTIS.

Thyroid hormone is essential for the normal function of virtually all tissues. The iodothyronine deiodinases catalyze the removal of an iodine residue from the pro-hormone thyroxine (T₄) molecule, thus producing either the active form triiodothyronine (T₃; activation) or inactive metabolites (reverse T₃; inactivation). Type I deiodinase (D1) catalyzes both reactions. Over the last years, several studies have attempted to understand the mechanisms of D1 function, underlying its effects on normal thyroid hormone metabolism and pathological processes. Although peripheral D1-generated T₃ production contributes to a portion of plasma T₃ in euthyroid state, pathologically increased thyroidal D1 activity seems to be the main cause of the elevated T₃ concentrations observed in hyperthyroid patients. On the other hand, D1-deficient mouse models show that, in the absence of D1, inactive and lesser iodothyronines are excreted in feces with the loss of associated iodine, demonstrating the scavenging function for D1 that might be particularly important in an iodine deficiency setting. Polymorphisms in the DIO1 gene have been associated with changes in serum thyroid hormone levels, whereas decreased D1 activity has been reported in the nonthyroid illness syndrome and in several human neoplasias. The current review aims at presenting an updated picture of the recent advances made in the biochemical and molecular properties of D1 as well as its role in human physiology.

The C3H/HeJ mouse presents an inherited type 1 deiodinase (D1) deficiency that results in elevated serum thyroxine (T₄), whereas TSH and tri-iodothyronine (T₃) concentrations are normal when compared with those in the C57BL/6J strain. Here, we evaluated the expression of the type 2 (D2), the other T₄-activating enzyme, in C3H mice. A comparative analysis revealed that D2 mRNA levels in C3H are similar to those in C57 animals. The D2 activity in C3H pituitary and brain are reduced when compared with those in the C57 strain (3.75 ± 1.08 vs 5.78 ± 0.33 and 0.17 ± 0.05 vs 0.26 ± 0.07 fmol/min per mg protein respectively). However, no differences on D2 activity levels were observed in the brown adipose tissue (BAT) between both strains (0.34 ± 0.06 vs 0.36 ± 0.09 fmol/min per mg protein). Experiments using different T₄ doses showed that higher levels of serum T₄ than those of the C3H mouse are required to downregulate D2 activity in this tissue. T₃ administration to euthyroid mice resulted in a two- to four-fold increase on D2 activity in BAT and brain of both strains, despite a marked decrease in BAT D2 transcripts and no changes in brain D2 mRNA levels. The increase in D2 activity was preceded by a decrease in serum T₄ levels, which appears to reduce D2 degradation. Indeed, administration of T₃ plus T₄ abolished the T₃-induced D2 upregulation. In conclusion, our results demonstrated that D2 activity is mainly regulated at posttranslational level in a tissue-specific manner. These observations further characterize and provide insights into the complex and dual regulatory role of the iodothyronines in D2 regulation.

The testis has been classically described as a thyroid hormone unresponsive tissue, but recent studies indicate that these hormones might play an important role in developing testes. We have previously demonstrated that type 2 iodothyronine deiodinase (D2), a thyroid hormone-activating enzyme, is expressed in adult rodent testis and that its activity is induced by hypothyroidism. Nevertheless, the precise location of D2 in testis is not known. The aim of the present work was to determine the testicular cell types in which D2 is expressed using real-time PCR analysis, in situ hybridization histochemistry, and determination of D2 activity in cell fractions isolated from adult euthyroid and/or hypothyroid rat testis. The D2 mRNA levels in germ cells were higher than those from somatic cells (6.94 ± 1.49 vs 2.32 ± 0.79 arbitrary units (au); P = 0.017). Hypothyroidism increased D2 expression in germ cells (6.94 ± 1.49 vs 8.78 ± 5.43 au, P = 0.002) but did not change D2 transcripts in somatic cells significantly (2.12 ± 0.79 vs 2.88 ± 1.39 au, P = 0.50). In situ hybridization analysis showed that D2 mRNA is specifically present in elongated spermatids undergoing differentiation, whereas other germ cell types and Sertoli cells of seminiferous epithelium and the interstitial cells were virtually negative for this enzyme. The enzyme activity measured in germ and somatic isolated cell fractions (0.23 ± 0.003 vs 0.02 ± 0.013 fmol/min per mg protein respectively; P < 0.001) further confirmed the real-time PCR and in situ hybridization results. Hence, our findings demonstrated that D2 is predominantly expressed in elongated spermatids, suggesting that thyroid hormone might have a direct effect on spermatogenesis in the adult rats.