Alan McGregor

Postpartum thyroid dysfunction in Mid Glamorgan

A high prevalence of postpartum thyroid dysfunction has been reported in several countries, but there have been no systematic studies of its prevalence in Britain. Among a group of 901 consecutive, unselected pregnant women thyroid autoantibodies were detected in 117 (13%) at booking. The clinical course of postpartum thyroid dysfunction, factors associated with its development, and its likely prevalence were defined in 100 of these women with thyroid antibodies and 120 women with no such antibodies who were matched for age. None of the women had a history of autoimmune thyroid disease. Normal reference ranges for thyroid function during pregnancy and post partum were established in the 120 women negative for thyroid antibodies. On the basis of these observations postpartum thyroid dysfunction was observed in 49 (22%) of the 220 women studied, and the prevalence in the total group of 901 women was estimated to be 16·7%. Thyroid dysfunction, mainly occurring in the first six months post partum, was usually transient and included both destruction induced hyperthyroidism and hypothyroidism. The development of the syndrome was significantly related to smoking more than 20 cigarettes a day and the presence of thyroid microsomal autoantibodies at booking. Of the 16 women with a family history of thyroid disease in whom thyroid microsomal autoantibody activity was detectable at booking, 11 developed thyroid dysfunction. Age, parity, presence of goitre at presentation, duration of breast feeding, and the sex and birth weight of the infant were not associated with the development of postpartum thyroid dysfunction. The mood changes experienced by women post partum may in part be associated with altered thyroid function during this time.

Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression

OBJECTIVE The incidence of depression in those with hypothyroidism is increased compared to healthy populations, though the mechanism for this Is unclear. We tested the hypothesis that central 5‐HT activity is reduced in hypothyroidism, and that this subsequently lowers the threshold for developing depression.

NEUROENDOCRINE RESPONSES TO D-FENFLURAMINE AND INSULIN-INDUCED HYPOGLYCEMIA IN CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is a disorder characterized by severe physical and mental fatigue and fatiguability of central rather than peripheral origin. We hypothesized that CFS is mediated by changes in hypothalamopituitary function and so measured the adrenocorticotrophic hormone (ACTH), cortisol, growth hormone, and prolactin responses to insulin-induced hypoglycemia, and the ACTH, cortisol, and prolactin responses to serotoninergic stimulation with dexfenfluramine in nondepressed CFS patients and normal controls. We have shown attenuated prolactin responses to hypoglycemia in CFS. There was also a greater ACTH response and higher peak ACTH concentrations (36.44 +/- 4.45 versus 25.60 +/- 2.78 pg ml), whereas cortisol responses did not differ, findings that are compatible with impaired adrenal cortical function. This study provided evidence for both pituitary and adrenal cortical impairment in CFS and further studies are merited to both confirm and determine more precisely their neurobiological basis so that rational treatments can be evolved.

The pathophysiology of the insulin‐like growth factor axis in fetal growth failure: a basis for programming by undernutrition?

Abstract. Recent evidence suggests that a number of adulthood conditions, including non‐insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra‐uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra‐uterine environment. Insulin‐like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP‐1 is antagonistic to the insulin‐like and growth promoting effects of IGF‐I, and IGFBP‐3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non‐starved small fetuses (SGA). IGF‐1 was significantly lower in the UPI group (n= 14, 7·8±0·6 μg l‐1), than in either the SGA group (n= 22, 31·4±3·5 μg l‐1, P= 0·0001) or the AGA group (n= 94, 36·3±1·9 μg l‐1, P= 0·0001). IGFBP‐3 showed similar changes (UPI: 682·6±50·0 μg l‐1; SGA: 831·9±55·5 μg l‐1; AGA: 847·7±19·8 μg l‐1). In contrast, IGFBP‐1 levels were significantly higher in the UPI group (312·4±57·5 μg l‐1) than in either the SGA group (132·6±39·5 μg l‐1, P= 0·009) or the AGA group (116·9±25·4 μg l‐1, P= 0·003), and the normal inverse relationship between IGFBP‐1 and insulin levels was lost in the UPI group. IGFBP‐2 levels showed a similar pattern (UPI: 2510·3±178·0 μg l‐1; SGA: 878·5±80·3μg l‐1, P= 0·0001; AGA: 791·6±27·0 μg l‐1, P= 0·0001). Thus, there are clear differences between the two groups of SGA fetuses. It is possible that in utero‘programming’ of the IGF/IGFBP axis, as a result of fetal undernutrition, may be important in the pathogenesis of disease in adulthood.

Thyroxine Replacement Increases Central 5-Hydroxytryptamine Activity and Reduces Depressive Symptoms in Hypothyroidism

Hypothyroidism is associated with both reduced central 5-HT function and an increased incidence of depression. This study tested the hypothesis that the reduced 5-HT function returns to normal with thyroxine replacement therapy. Seven hypothyroid patients were tested before and after adequate thyroxine replacement. Cortisol and prolactin responses to d-fenfluramine, a centrally acting 5-HT-releasing agent, were used as an index of central (hypothalamic) 5-HT responsiveness. 5-HT-mediated cortisol responses were significantly higher after thyroxine replacement. Basal prolactin levels were reduced, but 5-HT-mediated prolactin responses were not significantly higher after treatment, perhaps due to the pre-treatment responses being elevated by the direct stimulatory effects of hypothyroidism itself on pituitary prolactin secretion. Depressive symptomatology improved with thyroxine. TSH levels were positively related to depressive symptomatology, and inversely to cortisol responses. Depressive symptomatology was inversely related to cortisol responses. These findings thus provide further support that central 5-HT neurotransmission is affected by hypothyroidism. They also suggest that the reduction in 5-HT responsiveness is reversible with thyroxine replacement therapy.

Lateral cervical lymph node metastases in papillary thyroid cancer: a systematic review of imaging-guided and prophylactic removal of the lateral compartment.

Papillary thyroid cancer (PTC) is a common endocrine cancer and frequently presents with lymph node (LN) metastases. The frequency of LN metastases in the lateral compartment and their surgical removal are poorly defined. There are no prospective randomised controlled trials addressing an eventual outcome difference relating to the extent of the initial surgical approach. The aim of this study was to define the extent of lateral LN involvement and the role of imaging in identification of these metastatic LN.

Mapping of Autoantigenic Epitopes on Recombinant Thyroid Peroxidase Fragments Using the Polymerase Chain Reaction

Cloned cDNA templates of thyroid peroxidase (TPO) have been used in conjunction with the polymerase chain reaction (PCR) to express selected segments of the thyroid microsomal/peroxidase antigen (TMA/TPO) as recombinant protein in E. coli. Six small, different recombinant fragments averaging 120 amino acid residues and one large fragment (269 amino acids) of TPO which together encompass 80% of the extracellular region of the molecule have been produced and autoantibody (aAb) binding sites analysed by immunoblotting. A minimum of six independent, sequential antigenic determinants have been localized on the recombinant proteins and these map to the amino terminal, the central core region and the carboxyl terminal of the TPO molecule. More accurately, the six antigenic sites reside on overlapping recombinant TPO preparations termed R1a + R1b (residues 1 to 160) R1c (residues 145 to 250), R2b (residues 457 to 589), R3a (residues 577-677), R3b (residues 657-767) and R3c (residues 737-845). The large fragment of TPO termed R3 (residues 577-845) encompassing R3a, R3b and R3c also reacts with the aAbs. Different sera from patients with autoimmune thyroid disease contain antibodies to TMA/TPO which differ in their fine specificity. The use of recombinant molecular biological techniques together with PCR to prepare small segments of a large autoantigen as recombinant protein will now allow studies to progress on autoepitope mapping of the precise amino acid sequences of the TPO molecule with the use of synthetic peptides.

Unaltered thyroid function in mice responding to a highly immunogenic thyrotropin receptor: implications for the establishment of a mouse model for Graves' disease

Graves disease (GD) is a common disorder characterized by the presence of autoantibodies to the thyrotropin receptor. In the past, the exceedingly low expression of the thyrotropin receptor on thyrocytes has not allowed its purification in quantities sufficient to investigate the establishment of an animal model for this disease. In this study, we have purified the 398‐amino acid, extracellular region of the human thyrotropin receptor (TSH‐R.E) from insect cells using recombinant baculovirus, and explored its immunopathogenic properties in H‐2b,d,q,k,s strains of mice. The receptor preparation was highly immunogenic since it elicited strong specific proliferative T cell responses as well as IgG responses in all strains tested. In addition, hyperimmunization with TSH‐R.E induced (i) serum antibodies that blocked the binding of 125I‐TSH to its receptor, a common feature of GD autoantibodies; and (ii) IgG that reacted with a synthetic peptide (residues 32–54) from the N‐terminus of the receptor, a region implicated in the binding of thyroid stimulating antibodies. In SJL animals only, a weak antibody response to two other thyroid antigens, thyroglobulin and thyroid peroxidase, was also observed. The presence of these antibodies, however, was not accompanied by a detectable alteration in thyroid function as assessed by the measurement of serum TSH, T4 and iodine levels. Also mononuclear infiltration of the thyroid gland or morphological changes compatible with an activation state of thyrocytes were not apparent in TSH‐R‐challenged mice. In contrast, mice treated with the anti‐oxidant aminotriazole showed a dramatic increase in serum TSH levels and an activated follicular epithelium. These data demonstrate that a highly immunogenic TSH‐R.E in mice does not necessarily provide a proper stimulus for the induction of a hyper‐ or hypothyroid status as defined by hormonal or histological criteria. Main reasons for the inability to induce receptor‐specific antibodies that affect thyroid function such as those generated in GD are likely to be the inappropriate folding of the recombinant extracellular domain of the receptor, or the xenogeneic nature of the autoantigen.

Prediction of domain organisation and secondary structure of thyroid peroxidase, a human autoantigen involved in destructive thyroiditis

Organ specific autoimmune diseases are relatively common immunological disorders in man which include thyroid autoimmune disease, insulin‐dependent diabetes mellitus and myasthenia gravis. The target autoantigens in some of these diseases have recently been characterised. In thyroid autoimmune disease this includes the key enzyme, thyroid peroxidase (TPO), which is involved in the generation of thyroid hormone. Structural knowledge about autoantigens such as thyroid peroxidase will allow a greater understanding of the interaction between autoantigens and the aberrant immune response, and facilitate the development of strategies for antigen‐specific therapeutic manipulation. We report here a prediction of the secondary structure of thyroid peroxidase, together with the results of circular dichroic spectroscopy of a homologous purified enzyme. A combination of 3 secondary structure prediction programs has been used, following multiple sequence alignment, and TPO has been found to consist mainly of α‐helical conformation, with little β‐sheet present. This structure prediction, together with knowledge of the exon‐intron boundaries allows a model for the domain organisation of the TPO molecule to be proposed.

Evidence for 5-hydroxytryptamine1A receptor involvement in the control of prolactin secretion in man

The effects of pindolol pretreatment (2 days) on prolactin and cortisol responses to a single dose of (+)-fenfluramine (30 mg po) were examined in nine healthy male volunteers. Pindolol pretreatment attenuated the (+)-fenfluramine-induced increase in prolactin concentrations but failed to affect the (+)-fenfluramine-induced cortisol increase. These data provide evidence in support of 5-HT1A receptor involvement in the regulation of prolactin secretion but question its importance in the regulation of cortisol secretion in man