Presence Of Thyroid Hormone Receptors Research Articles

Thyroid Hormones and Their Role in Male Infertility: A Comprehensive Review

Thyroid hormones are pivotal regulators of various physiological processes, including reproductive function. While the impact of thyroid dysfunction on female fertility has been extensively studied, its association with male infertility has gained increasing recognition. This comprehensive review explores the role of thyroid hormones in male infertility, focusing on their effects on spermatogenesis, sperm quality, and reproductive outcomes. The review delves into the physiology of thyroid hormones, the presence of thyroid hormone receptors in the male reproductive system, and the influence of thyroid dysfunction on spermatogenesis and semen parameters. Additionally, it examines the molecular mechanisms underlying thyroid hormone action in the male reproductive system and discusses potential therapeutic strategies targeting thyroid hormone pathways to improve male fertility. Understanding the intricate relationship between thyroid hormones and male infertility is crucial for advancing diagnostic and therapeutic approaches in the management of male infertility associated with thyroid dysfunction.

Characterization of hypothalamo–pituitary–thyroid axis gene expression in the hypothalamus, pituitary gland, and ovarian follicles of turkey hens during the preovulatory surge and in hens with low and high egg production

Dysregulation of the preovulatory surge (PS) leads to lowered egg production. The hypothalamo–pituitary–thyroid (HPT) axis has been shown to influence plasma progesterone levels and follicle ovulation. The presence of thyroid hormone receptors (THR) in the reproductive axis suggests possible effects of thyroid hormone. To further understand the potential role of thyroid hormone on the PS, HPT axis plasma hormone concentrations and gene expression were characterized surrounding the PS in average egg producing hens (AEPH), low egg producing hens (LEPH), and high egg producing hens (HEPH) (n = 3 hens/group). Data were analyzed using the mixed models procedure of SAS, with significance indicated at P < 0.05. Average egg producing hens and HEPH displayed lower levels of triiodothyronine (T3) and higher levels of thyroxine (T4) inside of the PS, whereas LEPH showed inverse T3 and T4 levels relative to the PS. Expression of mRNA for hypothalamic thyrotropin-releasing hormone (TRH), pituitary thyrotropin (TSHB), and the main thyroid hormone metabolism enzyme (DIO2) were downregulated during the PS in AEPH and HEPH. Low egg producing hens displayed higher expression of mRNA for hypothalamic TRH as well as pituitary TSHB and DIO2 compared with HEPH. Average egg producing hens expression of THR mRNAs was upregulated during the PS in the hypothalamus but downregulated in the pituitary. High egg producing hens showed decreased expression of THR mRNAs in both the hypothalamus and pituitary when compared with LEPH. In ovarian follicles, THR mRNAs were more prevalent in the thecal layer of the follicle wall compared with the granulosa layer, and expression tended to decrease with follicle maturity. Minimal differences in follicular THR expression were seen between LEPH and HEPH, indicating that THR expression is unlikely to be responsible for steroid hormone production differences occurring between LEPH and HEPH. Generally, downregulation of the HPT axis was seen during the PS in AEPH and HEPH, whereas upregulation of the HPT axis was seen in LEPH. Further studies will be required to clarify the role of the HPT axis in the regulation of ovulation and egg production rates in turkey hens.

Impact of thyroid disease on testicular function.

Testis was considered unresponsive to thyroid hormone for a long time. However, like in animals, the presence of thyroid hormone receptors in different testicular cell types was demonstrated also in humans. Accordingly, thyrotoxicosis and hypothyroidism have remarkable effects on testicular function and more extensively on fertility. Thyrotoxicosis and hypothyroidism are associated with changes affecting the endocrine, sexual, or reproductive functions. Particularly, compared with controls, hyperthyroid patients have higher serum SHBG and lower free and bioavailable testosterone concentrations, a higher rate of astheno-zoospermia, oligo-zoospermia, and terato-zoospermia, and a higher prevalence of sexual disturbances, such as premature ejaculation. In hypothyroid patients, hormonal changes are in the opposite direction compared with hyperthyroid patients. Thyroid hormone regulates a number of functions in the testis, such as proliferation and differentiations of non-germ cells, steroidogenesis, and sperm motility. Furthermore, thyroid hormone regulates testicular redox status. Consequently, thyroid hormone excess or deficiency can affect testicular function at different levels. In view of the high prevalence of thyrotoxicosis and hypothyroidism, a considerable part of infertile patients may harbor overt or subclinical thyroid disease. Identification and management of thyrotoxicosis/hypothyroidism associated infertility needs the collaboration of andrologists, endocrinologists, gynecologists, and general practitioners.

Binding Properties of Thyroxine to Nuclear Extract from Sea Urchin Larvae

We previously reported that thyroid hormones are involved in the formation of the adult rudiment and adult-type skeleton in sea urchin larvae, as well as in the resorption of larval tissues. In the present study, to search for the presence of thyroid hormone receptor in sea urchin larvae, we performed a ligand-binding assay between radiolabeled thyroid hormones and nuclear extracts from the larvae of the sea urchin Hemicentrotus pulcherrimus. The presence of binding sites with a high affinity to thyroxine (T4) was detected in the nuclear extract, but not in the cytoplasmic fraction. The dissociation constants for the T4 binding to the nuclear extracts were estimated to be about 18 pM from the mesenchyme-blastula stage to the four-armed pluteus stage. The quantity of T4 binding sites in the nuclear extracts increased during larval development. These results suggest that the binding affinity to T4 in the nuclear extracts was caused by a putative nuclear thyroid hormone receptor in sea urchin larvae.

Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor–I expression and bone acquisition in mice

Understanding how bone growth is regulated by hormonal and mechanical factors during early growth periods is important for optimizing the attainment of peak bone mass to prevent or postpone the occurrence of fragility fractures later in life. Using genetic mouse models that are deficient in thyroid hormone (TH) (Tshr(-/-) and Duox2(-/-)), growth hormone (GH) (Ghrhr(lit/lit)), or both (Tshr(-/-); Ghrhr(lit/lit)), we demonstrate that there is an important period prior to puberty when the effects of GH are surprisingly small and TH plays a critical role in the regulation of skeletal growth. Daily administration of T3/T4 during days 5 to 14, the time when serum levels of T3 increase rapidly in mice, rescued the skeletal deficit in TH-deficient mice but not in mice lacking both TH and GH. However, treatment of double-mutant mice with both GH and T3/T4 rescued the bone density deficit. Increased body fat in the TH-deficient as well as TH/GH double-mutant mice was rescued by T3/T4 treatment during days 5 to 14. In vitro studies in osteoblasts revealed that T3 in the presence of TH receptor (TR) α1 bound to a TH response element in intron 1 of the IGF-I gene to stimulate transcription. In vivo studies using TRα and TRβ knockout mice revealed evidence for differential regulation of insulin-like growth factor (IGF)-I expression by the two receptors. Furthermore, blockade of IGF-I action partially inhibited the biological effects of TH, thus suggesting that both IGF-I-dependent and IGF-I-independent mechanisms contribute to TH effects on prepubertal bone acquisition.

Thyroglobulin gene is associated with premature ovarian failure

Variants of the thyroglobulin gene were significantly associated with premature ovarian failure in a Korean population. Three single nucleotide polymorphisms and one haplotype were found to be associated with a significant increase in the risk for premature ovarian failure.

Thyroid hormone controls the gene expression of HSV-1 LAT and ICP0 in neuronal cells

Various factors/pathways including hormonal regulation have been suggested to control HSV-1 latency and reactivation. Our computer analysis identified a DNA repeat containing thyroid hormone response elements (TRE) in the regulatory region of HSV-1 LAT. Thyroid hormone (T3) exerts its function via its receptor (TR), a transcriptional factor. Present study investigated the roles of TR and T3 on HSV-1 gene expression using cultured neuoroblastoma cell lines. We demonstrated that liganded TR activated LAT transcription but repressed ICP0 transcription in the presence of LAT TRE. The chromatin immunoprecipitation (ChIP) assays showed that TRs were recruited to LAT TREs independently of T3 and hyperacetylated H4 was associated with promoters that were transcriptionally active. In addition, ChIP results showed that a chromatin insulator protein CTCF was enriched at the LAT TREs in the presence of TR and T3. In addition, chromatin remodeling factor BRG1 complex is found to participate in the T3/TR-mediated LAT activation since overexpression of BRG1 enhanced the LAT transcription and the dominant negative mutant K785R abolished the activation. This is the first report revealing that TR exerted epigenetic regulation on HSV-1 ICP0 expression in neuronal cells and could have a role in the complex processes of HSV-1 latency/reactivation.

T3 receptors in human pituitary tumors

Objective: The purpose of this work was to investigate the synthesis of T3 receptors in human tumors of the anterior pituitary gland, its relationship with the hormone synthesized and/or secreted by the tumor and the post-surgical evolution of the patient.Methods: Patients were evaluated clinically and by magnetic nuclear resonance to classify the adenoma according to their size. Hormonal concentrations in sera were determined by radioimmunoassay. Immunohistochemistry of the pituitary hormones was performed in the tumors. Tumors were obtained at surgery and immediately frozen in ice, transported to the laboratory and stored at −70°C. Reverse transcription was performed with purified RNA from the tumors.Results: Out of 33 pituitary tumors, 29 had RNA for T3 receptors synthesis (88%). They were present in different histological specimens, the tumors were grades 1–4 according to their size, and there was no relationship between the size of the tumor and the presence of T3 receptor RNAs. The post-surgical evolution of the patient was mostly dependent on the size and not on the presence of T3 receptors.Discussion: The presence of thyroid hormone receptors in pituitary tumors is in line with two important characteristics of these tumors: they are histologically benign and well differentiated.

The role of thyroid hormone in testicular development and function

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 (T(3)) 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 T(3) 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.

Participation of Brahma-Related Gene 1 (BRG1)-Associated Factor 57 and BRG1-Containing Chromatin Remodeling Complexes in Thyroid Hormone-Dependent Gene Activation during Vertebrate Development

Multiple cofactors and chromatin remodeling complexes have been identified to contribute to the transcriptional activation regulated by thyroid hormone receptors (TRs) in vitro. However, their role and function during development in vivo remains to be elucidated. The total dependence of amphibian metamorphosis on thyroid hormone T3 provides a unique vertebrate model for studying the molecular mechanism of TR function in vivo. In this study, we show that the expression of Brahma-related gene 1 (BRG1), a chromatin-remodeling enzyme, is up-regulated at the climax of Xenopus laevis metamorphosis, whereas BRG1-associated factor 57 (BAF57), a BRG1-binding protein in BRG1-containing chromatin remodeling complexes, is constitutively expressed during development. Consistently, T3 treatment of premetamorphic tadpoles led to up-regulation of the expression of BRG1 but not BAF57. Studies using a reconstituted T3-dependent Xenopus oocyte transcription system, where we could study TR function in the context of chromatin, revealed that BRG1 enhances the transcriptional activation by ligand-bound TRs in a dose-dependent manner, whereas a remodeling-defective BRG1 mutant inhibited the activation, suggesting that this process relies on chromatin remodeling. Additional studies showed that BAF57 interacted with BRG1 in oocytes and enhanced gene activation by TR cooperatively with BRG1 in vivo. Chromatin immunoprecipitation revealed that BAF57 was recruited to the TR-regulated promoter in the presence of TR and T3. Together, these findings suggest a role of BRG1/BAF57-containing chromatin remodeling complexes in TR-regulated gene expression during postembryonic development.

Control of dendritic cell maturation and function by triiodothyronine

Accumulating evidence indicates a functional crosstalk between immune and endocrine mechanisms in the modulation of innate and adaptive immunity. However, the impact of thyroid hormones (THs) in the initiation of adaptive immune responses has not yet been examined. Here we investigated the presence of thyroid hormone receptors (TRs) and the impact of THs in the physiology of mouse dendritic cells (DCs), specialized antigen-presenting cells with the unique capacity to fully activate naive T cells and orchestrate adaptive immunity. Both immature and lipopolysaccharide-matured bone marrow-derived DCs expressed TRs at mRNA and protein levels, showing a preferential cytoplasmic localization. Remarkably, physiological levels of triiodothyronine (T3) stimulated the expression of DC maturation markers (major histocompatibility complex II, CD80, CD86, and CD40), markedly increased the secretion of interleukin-12, and stimulated the ability of DCs to induce naive T cell proliferation and IFN-gamma production in allogeneic T cell cultures. Analysis of the mechanisms involved in these effects revealed the ability of T3 to influence the cytoplasmic-nuclear shuttling of nuclear factor-kappaB on primed DCs. Our study provides the first evidence for the presence of TRs on bone marrow-derived DCs and the ability of THs to regulate DC maturation and function. These results have profound implications in immunopathology, including cancer and autoimmune manifestations of the thyroid gland at the crossroads of the immune and endocrine systems.

Immunodetection of Thyroid Hormone Receptor (Alpha1/Alpha2) in the Rat Uterus and Oviduct

The aim of this study was to investigate the immunolocalization and the existence of thyroid hormone receptors (THR) (alpha1/alpha2) in rat uterus and oviduct. For this purpose 6 female Wistar albino rats found in estrous period were used. Tissue samples fixed in 10% neutral formalin were examined immunohistochemically. Sections were incubated with primary mouse-monoclonal THR (alpha1/alpha2) antibody. In uterus, THR (alpha1/alpha2) immunoreacted strongly with uterine luminal epithelium, endometrial gland epithelium and endometrial stromal cells and, moderately with myometrial smooth muscle. In oviduct, they were observed moderately in the epithelium of the tube and the smooth muscle cells of the muscular layer.In conclusion, the presence of THR in uterus and oviduct suggests that these organs are an active site of thyroid hormones.

Thyroid hormone and astrocyte morphogenesis

Astrocyte cells clearly play a role in neural development, but nowadays their total action is seen as a far wider one. Recent findings consider them as stem cells, involved in the control of most facets of functional neural networks. Astrocytes play a central role in thyroid hormone metabolism in the brain, being the principal transporters of thyroxine from the blood, responsible for its conversion to 3,5,3'-triiodothyronine and hence supplying the neural tissues with the biologically active form of the hormone. Specific thyroid hormone transporters play an essential role in this regulatory system. The presence of thyroid hormone receptors has been demonstrated in cultured astrocytes. Furthermore, thyroid hormone regulates several aspects of astrocyte differentiation and maturation, including the production of extracellular matrix proteins and growth factors, and thus controls neuronal growth and neuritogenesis. Therefore, astrocytes are currently suggested as important mediators of thyroid hormone in neuronal development.

Influence of thyroid hormone receptors on breast cancer cell proliferation

Background: The involvement of thyroid hormones in the development and differentiation of normal breast tissue has been established. However, the association between breast cancer and these hormones is controversial. Therefore, the objective of the present study was to determine the protein expression pattern of thyroid hormone receptors in different human breast pathologies and to evaluate their possible relationship with cellular proliferation.Patients and methods: The presence of thyroid hormone receptors was evaluated by immunohistochemistry and western blot analysis in 84 breast samples that included 12 cases of benign proliferative diseases, 20 carcinomas in situ and 52 infiltrative carcinomas.Results: TR-α was detected in the nuclei of epithelial cells from normal breast ducts and acini, while in any pathological type this receptor was located in the cytoplasm. However, TR-β presented a nuclear location in benign proliferative diseases and carcinomas in situ and a cytoplasmatic location in normal breast and infiltrative carcinomas. The highest proliferation index was observed in carcinomas in situ, although in infiltrative carcinomas an inverse correlation between this index and the TR-α expression was encountered.Conclusions: The results of this study reveal substantial changes in the expression profile of thyroid hormone receptors suggesting a possible deregulation that could trigger breast cancer development.

Thyroid Hormone Response Element Sequence and the Recruitment of Retinoid X Receptors for Thyroid Hormone Responsiveness

Thyroid hormone receptors (TRs) are transcription factors that bind to thyroid hormone response elements (TREs) in the regulatory regions of target genes. TRs are thought to activate transcription primarily as heterodimers with retinoid X receptors (RXRs), with RXR binding upstream to the two directly repeated half-sites in a typical TRE. However, given that TRs and RXRs prefer to bind to different DNA sequences (T(A/G)AGGTCA and GGGGTCA), we postulate that only certain TREs require RXR-TR heterodimerization, depending on the TRE sequence. We have tested this hypothesis by comparing in Saccharomyces cerevisiae the functional activity of TR +/- RXR on 10 naturally occurring mammalian TREs. S. cerevisiae was used as a model system because yeast lack endogenous nuclear receptors and thus can be manipulated to express TRs and/or RXRs. We first studied ligand-independent reporter gene activation, which reflects the activity of the activator function 1 (AF-1) domain. The 10 TREs formed a continuous spectrum from being fully dependent on RXR for TR AF-1 activity to being essentially independent of RXR. Relative independence of RXR generally was seen when the TRE upstream half-site has a TA or TG 5' to the core hexamer. Gel mobility shift assays revealed that functional independence of RXR correlates with the strong binding of TR alone, whereas more RXR dependence correlates with higher binding of RXR-TR heterodimers. Restoration of ligand-dependent (AF-2 domain) reporter gene activation was achieved by expression of the coactivator TIF2. This ligand-induced stimulation was stronger in the presence of TR alone than with RXR plus TR, suggesting a preference for TIF2 activation of TR homodimers. Overall the data support the notion that the TRE sequence plays an important role in determining the nuclear hormone receptor and coactivator requirements for TR action.

The Human Fetal Retinal Pigment Epithelium: A Target Tissue for Thyroid Hormones

Thyroid hormone (T₃) has previously been shown to regulate visual function in experimental animals and humans. To determine if T₃ exerts direct effects on retinal function, cultured human fetal retinal pigment epithelial (RPE) cells were tested for the presence of thyroid hormone receptors (TRs) and T₃ responses. Using TR-isoform-specific reverse-transcriptase polymerase chain reaction techniques, mRNA was detected for α1, α2 and β1 TR isoforms. Immunohistochemistry using a polyclonal antibody that simultaneously recognizes α1, α2 and β1 TRs showed nuclear staining of the fetal RPE. Specific binding of ¹²⁵I-T₃ to RPE cell nuclear extracts was detected, and Scatchard analysis revealed a K_d of 110 pM. To determine if RPE cells can respond to T₃, hyaluronic acid (HA) levels in cell culture media were measured after 2, 4 or 6 days of growth in medium containing 10^–7 M T₃. T₃ inhibited accumulation of HA in the cell culture medium of RPE cells. This effect was not evident at 2 days, but at 4 days there was 42.8% less HA in cell culture medium of RPE cells grown in 10^–7 M T₃ (p < 0.01, t test). The effect persisted through 6 days, when there was 46.3% less HA in cell culture medium of RPE cells grown in 10^–7 M T₃ (p < 0.001, t test). The data indicate that human fetal RPE cells are a direct target for thyroid hormones.

Thyroid Hormone Response Element Architecture Affects Corepressor Release from Thyroid Hormone Receptor Dimers

Thyroid hormone receptors are ligand-modulated transcription factors that can repress or activate transcription depending upon the absence or presence of thyroid hormone and the nature of the hormone response element to which the receptors are bound. The ability of thyroid hormone receptors to repress transcription in the absence of ligand is thought to be due to associations with nuclear hormone receptor corepressors. Ligand binding by the thyroid hormone receptor is believed to dissociate these corepressors and recruit coactivators to promote transcription from target promoters. We hypothesize that variations in response element architecture may influence both the association and dissociation of corepressors from DNA-bound thyroid hormone receptors. Using a chimeric corepressor, we find that ligand alone does not fully relieve corepressor-mediated repression, particularly in the presence of thyroid hormone receptor and its heterodimerization partner, the retinoid X receptor. Interestingly, the steroid receptor coactivator 1 together with ligand is able to mediate full release of corepression, but this relief is dependent upon the architecture of the response element to which the nuclear receptor dimer-corepressor complex is bound. These studies suggest that other cellular factors in addition to ligand may be required for the release of corepressors from thyroid hormone receptor dimers.

L-thyroxine directly affects expression of thyroid hormone-sensitive genes: regulatory effect of RXR β

l-thyroxine (T4) has been considered mainly a prohormone, the hormonal action of which is related to its conversion to 3,5,3′-triiodothyronine (T3) in peripheral tissues. In this study we investigated in transient transfection assays whether T4 might directly affect the expression of thyroid hormone (TH) sensitive genes. The reporter construct ME-TRE-TK-CAT or TSH-TRE-TK-CAT containing the nucleotide sequence of the TH response element (TRE) of either malic enzyme (ME) or TSH β genes, was transfected with either TH receptor (TR) α alone or in combination with retinoid X receptor (RXR) β into NIH3T3 cells. Addition of 100 nM T4 to the culture medium in the presence of TR α increased the basal level of ME-TRE-TK-CAT expression by 4.5-fold. T4 action was due to a direct interaction with TR α and not to its conversion to T3, since T4 effect persisted in the presence of 5′-deiodinase inhibitors (propylthiouracil, iopanoic acid) effectively preventing T3 generation, as assessed by the absence of T3 by HPLC in the cellular extracts of transfected cells. In a dose-response study half-maximal stimulation by T4 was achieved at a concentration of 100 nM, whereas 50% of maximal induction was produced by 1 nM T3 and 6 nM triiodothyroacetic acid (TRIAC). Coexpression of RXR β greatly enhanced the transcriptional activity of the ME-TRE-TK-CAT gene when either T3, T4 or TRIAC was added to the culture medium of NIH3T3 cells, but established a hormonal hierarchy in the reporter activation different than that observed in the presence of TR α alone (TRIAC>T3≥T4, instead of T3>TRIAC>T4). T4 at a concentration of 100 nM could activate the TH/TR-dependent down-regulation mediated by the negative TSH-TRE, although at a lower level than that obtained with similar concentrations of T3 (35 and 55% inhibition, respectively). Our results demonstrate that, in addition to the action mediated through its monodeiodination to T3, T4 exerts a direct effect on genes that are either positively or negatively regulated by TH. Moreover, RXR β, forming heterodimers with TRs, appeared to exert a central role in modulating the sensitivity of TH-responsive genes to different iodothyronines.

Interactions of Estrogen- and Thyroid Hormone Receptors on a Progesterone Receptor Estrogen Response Element (ERE) Sequence: a Comparison with the Vitellogenin A2 Consensus ERE

The identification of hormone response elements in the promoter regions of hormonally regulated genes has revealed a striking similarity between the half-site of the estrogen-response element (ERE) and a consensus sequence constituting the thyroid hormone-response element. Because of the potential for thyroid hormone (T3) to affect estrogen (E)- and progesterone-dependent female reproductive behavior via EREs, we have begun to investigate the activity of an ERE identified in the progesterone receptor (PR) proximal promoter and its interactions with the estrogen receptor (ER) and thyroid hormone receptors (TR). In addition, we have compared ER and TR interactions on the PR ERE construct with that of the vitellogenin A2 (vit A2) consensus ERE. Electrophoretic mobility shift assays demonstrated that TR binds to the PR ERE as well as to the consensus ERE sequence in vitro. Further, these two EREs were differentially regulated by T3 in the presence of TR. T3 in the presence of TRα increased transcription from a PR ERE construct ∼5-fold and had no inhibitory effect on E induction. Similarly, T3 also activated a β-galactosidase reporter construct containing PR promoter sequences spanning −1400 to +700. In addition, the TR isoforms β1 and β2 also stimulated transcription from the PR ERE construct by 5- to 6-fold. A TRα mutant lacking the ability to bind AGGTCA sequences in vitro failed to activate transcription from the PR ERE construct, demonstrating dependence on DNA binding. In contrast to its actions on the PR ERE construct, TRα did not activate transcription from the vit A2 consensus ERE but rather attenuated E-mediated transcriptional activation. Attenuation from the vit A2 consensus ERE is not necessarily dependent on DNA binding as the TRα DNA binding mutant was still able to inhibit E-dependent transactivation. In contrast to TRα, the isoforms TRβ1 and TRβ2 failed to inhibit E-induced activation from the vit A2 consensus ERE. These results demonstrate that the PR ERE construct differs from the vit A2 consensus ERE in its ability to respond to TRs and that divergent pathways exist for activation and inhibition by TR. Since ERs, PRs, and TRs are all present in hypothalamic neurons, these findings may be significant for endocrine integration, which is important for reproductive behavior.

The expression of thyroid hormone receptors in human bone

The mechanism of action of thyroid hormones on bone is poorly understood. Thyroid hormones may act on bone cells either indirectly by increasing secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), or directly by influencing target genes via specific nuclear receptors. The presence of thyroid hormone receptors (TRs) has been demonstrated in human and rodent osteoblast-like cells and cell lines and recently in osteoclasts derived from an osteoclastoma in vitro. However, their presence in human bone in situ has not been reported. We have used specific polyclonal antibodies to TR-α1, -α2, and β1 to investigate the expression of these receptors in sections of human osteophytes and heterotopic bone. Osteoblasts and osteoclasts were identified by alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), respectively, whereas chondrocytes were identified morphologically. At sites of endochondral and intramembranous bone formation, TR-β1 and the splice variant -α2 were widely expressed by proliferating, mature, and hypertrophic chondrocytes and also in cells within the fibrous tissue and at the bone forming surfaces, respectively. They were also detected in osteoblasts, osteoclasts, and a few osteocytes at sites of bone remodeling. In contrast, TR-α1 was the least expressed and was present mainly in osteoblasts at remodeling sites and in a few mature and undifferentiated chondrocytes. Our results show, for the first time, the presence and distribution of TRs in human bone in situ and suggest that the skeletal actions of thyroid hormones may be mediated via these receptors. Further studies are required to define the role of the individual receptor isoforms in bone metabolism.