Thyroid disease is common, affecting around 2% of women and 0.2% of men in the UK. Our understanding of the effects of thyroid hormones under physiological circumstances, as well as in pathological conditions, has increased dramatically during the last two centuries and it has become clear that overt thyroid dysfunction is associated with significant morbidity and mortality. Both hypo-and hyperthyroidism and their treatments have been linked with increased risk from cardiovascular disease and the adverse effects of thyrotoxicosis in terms of osteoporosis risk are well established. Although the evidence suggests that successful treatment of overt thyroid dysfunction significantly improves overall survival, the issue of treating mild or subclinical hyper- and hypothyroidism remains controversial. Furthermore, the now well-established effects of thyroid hormones on neurodevelopment have sparked a whole new debate regarding the need to screen pregnant women for thyroid function abnormalities. This review describes the current evidence of the effects of thyroid hormone on the cardiovascular, skeletal and neurological systems, as well as the influence of thyroid diseases and their treatments on the development of malignancy. Furthermore we will describe some recent developments in our understanding of the relationship between thyroid status and health.
K Boelaert and J A Franklyn
J. A. Franklyn and M. C. Sheppard
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham b15 2th
received 1 November 1987
Thyrotrophin (TSH) is one of a family of glycoprotein hormones which includes the pituitary hormones follicle-stimulating hormone and luteinizing hormone, and placental chorionic gonadotrophin. Each hormone is composed of two dissimilar, non-covalently linked glycosylated subunits, α and β. The mammalian genome contains a single gene encoding the α-subunit which is common to each of the glycoprotein hormones (Fiddes & Goodman, 1981). In contrast, the β-subunits of each hormone are encoded by different genes and confer biological and immunological specificity upon the intact dimer.
The gene encoding the β-subunit of TSH has been assigned to chromosome 1 in man (Fukushige, Murotsu & Matsubara, 1986) and chromosome 3 in the mouse (Kourides, Barker, Gurr et al. 1984). The α-gene, unlike the β-gene, has been assigned in the mouse to chromosome 4 (Kourides et al.
Vicki E Smith, Jayne A Franklyn and Christopher J McCabe
Pituitary tumor-transforming gene (PTTG)-binding factor (PBF; PTTG1IP) was initially identified through its interaction with the human securin, PTTG. Like PTTG, PBF is upregulated in multiple endocrine tumours including thyroid cancer. PBF is believed to induce the translocation of PTTG into the cell nucleus where it can drive tumourigenesis via a number of different mechanisms. However, an independent transforming ability has been demonstrated both in vitro and in vivo, suggesting that PBF is itself a proto-oncogene. Studied in only a limited number of publications to date, PBF is emerging as a protein with a growing repertoire of roles. Recent data suggest that PBF possesses a complex multifunctionality in an increasing number of tumour settings. For example, PBF is upregulated by oestrogen and mediates oestrogen-stimulated cell invasion in breast cancer cells. In addition to a possible role in the induction of thyroid tumourigenesis, PBF overexpression in thyroid cancers inhibits iodide uptake. PBF has been shown to repress sodium iodide symporter (NIS) activity by transcriptional regulation of NIS expression through the human NIS upstream enhancer and further inhibits iodide uptake via a post-translational mechanism of NIS governing subcellular localisation. This review discusses the current data describing PBF expression and function in thyroid cancer and highlights PBF as a novel target for improving radioiodine uptake and thus prognosis in thyroid cancer.
N. K. Green, J. A. Franklyn, J. A. O. Ahlquist, M. D. Gammage and M. C. Sheppard
The effect of tri-iodothyronine (T3) treatment on myocardial levels of α and β myosin heavy chain (MHC) mRNAs in the rat was defined in vivo and in vitro. Dose–response experiments were performed in intact hypothyroid and euthyroid rats; in addition, studies in vitro examined the effect of T3 on MHC mRNAs in neonatal cardiac myocytes in primary culture. Specific α and β MHC mRNAs were determined by Northern blot and dot hybridization to oligonucleotide probes complementary to the 3′ untranslated regions of the MHC genes. An increase in myocardial β MHC mRNA was demonstrated in hypothyroidism, accompanied by a reduction in α MHC mRNA. Marked differences in the sensitivity of α and β MHC mRNAs to T3 replacement were found; a dose-dependent increase in α mRNA was evident at 6 h after T3 treatment, in the absence of consistent effects on β mRNA, whereas 72 h after T3 replacement was commenced, stimulatory effects of T3 on α MHC mRNA, evident at all doses, were accompanied by a dose-dependent inhibition of β MHC mRNA. No effect of thyroid status on actin mRNA was found, indicating the specificity of MHC gene regulation. T3 treatment of cardiac myocytes in vitro exerted similar actions on MHC mRNAs to those found in vivo, with a more marked influence on α than β MHC mRNA. These studies of the action of T3 in vivo and in vitro have thus demonstrated specific effects of T3 on pretranslational regulation of the α and β MHC genes, influences which differ not only in terms of stimulation or inhibition, but also in magnitude of effect.
Journal of Endocrinology (1989) 122, 193–200
J. R. E. Davis, T. C. Lynam, J. A. Franklyn, K. Docherty and M. C. Sheppard
Thyroid hormones may regulate prolactin gene transcription. We have previously found that phenytoin inhibits tri-iodothyronine (T3) nuclear binding, and have suggested that phenytoin may act as a partial T3 agonist. We have therefore investigated the effects of phenytoin and T3 on prolactin release and gene transcription, using the technique of cytoplasmic dot hybridization with complementary DNA probes to estimate prolactin messenger (m) RNA concentrations in cytoplasm from cultured rat pituitary cells.
Tri-iodothyronine treatment led to a small but significant fall in prolactin release by 72 h, but caused marked dose- and time-dependent reductions in prolactin mRNA levels at 48–72 h. Phenytoin, however, caused more rapid falls in both prolactin release and mRNA concentrations. Neither T3 nor phenytoin significantly altered GH mRNA levels. These studies suggest effects of phenytoin similar, but not identical, to those of T3 in the lactotroph.
J. Endocr. (1986) 109, 359–364
J. A. Franklyn, J. R. E. Davis, D. B. Ramsden and M. C. Sheppard
Circulating free thyroid hormone concentrations are reduced in subjects taking long-term phenytoin, a finding at variance with their euthyroid clinical state and normal serum TSH concentration. It is suggested, therefore, that phenytoin may modify the cellular effects of thyroid hormones.
In order to examine the influence of phenytoin on thyroid hormone action in the pituitary gland we studied its effect on the binding of tri-iodothyronine (T3) to isolated nuclei prepared from rat anterior pituitary tissue. Phenytoin inhibited the nuclear binding of T3 in a dose-dependent fashion. Phenytoin also partially inhibited thyrotrophin-releasing hormone-stimulated TSH release from cultured rat anterior pituitary cells. These studies provide evidence for a direct effect of phenytoin on the thyrotroph mediated via nuclear T3 receptor binding.
J. Endocr. (1985) 104, 201–204
J.A. Franklyn, M. Wilson, J.R. Davis, D.B. Ramsden, K. Docherty and M.C. Sheppard
We have reported previously the effect of thyroid status in vivo on pituitary cytoplasmic concentrations of messenger RNA (mRNA) encoding the thyrotrophin (TSH) β-subunit (Franklyn, Lynam, Docherty et al, 1985). Studies in vitro of the regulation of TSH β gene transcription have been confined to thyrotrophic tumour cells. We now report the demonstration of TSH β-subunit mRNA in non-tumorous rat pituitary cells in primary culture. Treatment of cells with thyrotrophin-releasing hormone (TRH) and with forskolin resulted in a marked increase in cellular concentration of TSH β-mRNA. These results suggest that TRH exerts a direct effect on the pretranslational events involved in TSH synthesis and further that the adenylate cyclase system may be involved in the regulation of synthesis. We have thus described a novel system for the study of TSH β-subunit gene expression in normal rat pituitary cells in vitro.
D. F. Wood, J. A. Franklyn, K. Docherty, D. B. Ramsden and M. C. Sheppard
Thyroid hormones are important regulators of GH synthesis and secretion. In this study we have made a detailed examination of the time-course of the effects of hypothyroidism and tri-iodothyronine (T3) replacement in the intact rat on GH gene expression in the anterior pituitary gland. Changes in pituitary cytoplasmic GH messenger (m)RNA levels were compared with total pituitary GH content and serum GH concentration during the development of hypothyroidism and following short-term T3 replacement in vivo. Hypothyroidism was associated with a fall in pituitary GH mRNA levels. Treatment of hypothyroid animals with T3 rapidly stimulated GH mRNA levels to values above those seen in euthyroid controls. The reduction in GH mRNA levels seen during the development of hypothyroidism was accompanied by a fall in serum GH and pituitary GH content, both of which were partially restored by T3 replacement. Thus thyroid hormone replacement in hypothyroidism rapidly stimulates GH mRNA synthesis, which is followed by the gradual restoration of pituitary GH stores and serum GH concentration.
J. Endocr. (1987) 112, 459–463
J. A. Franklyn, T. Lynam, K. Docherty, D. B. Ramsden and M. C. Sheppard
Thyroid hormones may directly regulate gene expression in the anterior pituitary. In order to examine this possibility we have studied the effect of hypothyroidism in the rat on pituitary cytoplasmic concentrations of messenger RNA (mRNA) encoding thyrotrophin (TSH) β and α subunits, prolactin and GH. We demonstrated a marked increase in TSH β and α subunit mRNA, accompanied by a decrease in GH mRNA, in the hypothyroid state, changes largely reversed by thyroid hormone replacement. We have thus shown a direct influence of thyroid status on the pretranslational events occurring in pituitary hormone synthesis. The simultaneous rise in cytoplasmic TSH β and α mRNA levels and fall in GH mRNA in hypothyroidism suggests that thyroid status exerts a differential effect on the expression of these genes.
J. Endocr. (1986) 108, 43–47
N. K. Green, M. D. Gammage, J. A. Franklyn and M. C. Sheppard
Effects of thyroid status on expression of a variety of myocardial genes, such as those encoding contractile proteins, have been reported, as well as interactions between thyroid hormones and developmental and haemodynamic regulation of contractile protein synthesis. In addition, it is clear that developmental and haemodynamic factors regulate expression of specific proto-oncogenes, including c-myc, c-fos and H-ras, in the myocardium but the effect of thyroid status on such proto-oncogene products, which are proposed to play a critical signal-transducing role in the heart, has been previously unexplored.
In order to determine whether changes in thyroid status are associated with changes in expression of these putative intracellular signals, we examined the effect of hypothyroidism and tri-iodothyronine (T3) treatment on myocardial levels of c-myc, c-fos and H-ras mRNAs in the rat. The induction of hypothyroidism was associated with a marked increase in myocardial c-myc, c-fos and H-ras mRNAs, changes reversed by 72 h of T3 replacement. Administration of T3 to euthyroid rats had no significant effect on myocardial c-myc or c-fos mRNAs, but inhibition of H-ras mRNA by T3 was evident. These observations demonstrating influences of thyroid status on expression of specific proto-oncogenes suggest that thyroid hormones, as well as exerting direct effects on expression of functionally important myocardial genes, also interact with the cellular transduction pathways mediated by the products of the c-myc, c-fos and H-ras genes.
Journal of Endocrinology (1991) 130, 239–244