Growth hormone response to thyrotrophin releasing hormone in women with polycystic ovarian syndrome.

Recent clinical studies have suggested that women with polycystic ovarian syndrome (PCOS) may have disturbances of growth hormone (GH) kinetics and the GH/insulin-like growth factor (IGF)-I system. The knowledge that in various metabolic abnormalities there is a paradoxical sensitivity of pituitary somatotrophs to thyrotrophin releasing hormone (TRH) administration led to this investigation of the GH secretory response to TRH in women with PCOS. Twenty-four women with PCOS and 18 control women were studied. TRH was given as a single i.v. injection (time 0) and blood samples for GH measurements were obtained at -15, 0, 15, 30, 60 and 90 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (Deltamax). The GH response to TRH (mean +/- SEM) was greater in women with PCOS (Deltamax 2.47 +/- 1. 73 versus 0.47 +/- 0.06 ng/ml, P < 0.05 and GH AUC 8.05 +/- 2.10 versus 2.58 +/- 0.18 ng/ml/90 min, P < 0.05). According to GH response to TRH, two PCOS subgroups were identified: (i) normal responders (n = 14) who showed Deltamax GH response (0.36 +/- 0.06 ng/ml)and GH AUC (1.93 +/- 0.64 ng/ml/90 min) similar to that in the controls and (ii) over-responders (n +/- 10) who showed a paradoxical increase in GH concentrations in response to TRH (Deltamax GH response 5.43 +/- 1.27 ng/ml and GH AUC 16.62 +/- 3.51 ng/ml per 90 min) that was significantly higher than in normally responding PCOS patients (P < 0.0001) or in controls (P < 0.0001). These data demonstrate an enhanced GH response to TRH administration in a subgroup of women with PCOS.     

Physiological relevance of thyroid stimulating hormone and thyroid stimulating hormone receptor in tissues other than the thyroid

Decades of research have provided strong evidence for a reciprocal relationship between the immune system and hormones of the hypothalamus-pituitary-thyroid (HPT) axis. Thyroid stimulating hormone (TSH), in particular, has been shown to have a variety of immune-regulating cytokine-like activities that can influence the outcome of T cell development in the thymus and intestine, and can affect the magnitude of antibody and cell-mediated responses of peripheral lymphocytes. Production of TSH and the expression of the TSH receptor are widely but selectively distributed across many different types of hematopoietic cells in the bone marrow, as well as among subsets of dendritic cells, monocytes and lymphocytes in the spleen and lymph nodes. In addition to their role in immunity, the involvement of TSH-producing hematopoietic cells in the microregulation of thyroid hormone activity represents a novel and potentially important aspect of the TSH-mediated immune-endocrine circuit.     

Restoration of disturbed respiration in cats by thyrotrophin releasing hormone

Department of Physiology of Man and Animals, Biological Faculty, M. V. Lomonosov Moscow University. (Presented by Academician of the Academy of Medical Sciences of the USSR I. P. Ashmarin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 106, No. 7, pp. 17–19, July, 1988.     

Luteinizing hormone responses to luteinizing hormone releasing hormone (LHRH) in acute mania and the effects of lithium on LHRH and thyrotrophin releasing hormone tests in volunteers

The endocrine responses to Luteinizing Hormone Releasing Hormone (LHRH) of eight drug-free males with mania were determined. Basal levels of Luteinizing Hormone (LH) and the plasma levels following injection of LHRH were elevated in patients compared with controls; Follicle Stimulating Hormone (FSH) and testosterone were not different. Elevated levels of LH have been described previously in recovered manic patients and have been suggested to be state-independent features of mania. In order to clarify the status of this finding, the effects of lithium administration upon hormone responses to LHRH in six male volunteers were also investigated, together with the effects upon Thyrotrophin Releasing Hormone (TRH) stimulation of Thyroid Stimulating Hormone (TSH) and prolactin release. Lithium increased the basal levels of LH and levels after injection of LHRH without effect upon FSH and testosterone. Lithium also increased basal and TRH stimulated release of TSH and basal prolactin levels. Lithium was without effect upon prolactin responses to TRH. The results are discussed in relation to current information on the mechanism of lithium's action. The implications for neuroendocrine work on recovered patients taking lithium are also explored.     

Comparison of two triiodothyronine uptake techniques for the assessment of thyroid function

The present study was designed to compare the Thyopac and Triosorb triiodothyronine uptake tests. A normal range was established for the two procedures. Neither test was affected by iodine-containing drugs or contrast media but abnormal results were obtained during pregnancy and in subjects receiving oestrogens. Both tests proved satisfactory in the diagnosis of hypo- and hyperthyroidism, giving results consistent with clinical assessment and with serum protein-bound iodine determinations. The Thyopac procedure was preferred for a number of reasons. It requires less plasma; it is slightly simpler and quicker and it is not time dependent.     

Exaggerated and prolonged thyrotrophin releasing hormone (TRH) test responses in tertiary hypothyroidism.

A 60 year old man with panhypopituitarism due to a large meningioma and prolonged and exaggerated thyroid stimulating hormone (TSH) responses is described. Initial investigations showed a subnormal urinary free cortisol concentration, a low serum cortisol taken at 0900 hours, and a low free T4 concentration. The TSH was towards the upper end of the normal range. Subsequently pituitary function tests showed subnormal production of luteinising hormone in response to luteinising hormone releasing hormone (LHRH) and a short synacthen test with a low 30 minute cortisol value. Long synacthen testing showed a normal response at four days, confirming that the abnormalities were due to a pituitary or hypothalamic cause. A computed tomogram showed a large meningioma compressing the hypothalamus, pituitary, and temporal lobe. TRH testing showed a prolonged and exaggerated response, consistent with tertiary hypothyroidism.     

Presence of immunoreactive corticotropin releasing hormone in thyroid lesions.

Corticotropin-releasing hormone (CRH) functions as a regulator of the hypothalamic-pituitary-adrenal axis and coordinator of the stress response. Immunoreactive CRH (IrCRH) is also produced in a variety of inflammatory sites, where this peptide acts as a proinflammatory cytokine. To detect CRH in autoimmune thyroid disease as well as in disorders that may be associated with an inflammatory reaction within this gland, we examined immunohistochemically 45 thyroid lesions, including 12 nodular goiters, 9 cases of Hashimoto thyroiditis, 6 follicular adenomas, 4 follicular and 8 papillary carcinomas, 4 Hürthle cell tumors, 1 medullary cancer, and 1 insular thyroid carcinoma. We also examined the presence of IrCRH in the adjacent normal thyroid parenchyma. The avidin-biotin complex method was employed on formalin-fixed, paraffin-embedded tissue, using a highly specific, affinity-purified polyclonal rabbit anti-CRH antibody. Granular cytoplasmic immunostaining of follicular cells was observed in 100% of the cases of Hashimoto thyroiditis, 77% of the neoplasms and 42% of goiters. The intensity of the staining was more pronounced in Hashimoto thyroiditis and Hürthle cell tumors, whereas the remaining lesions exhibited a heterogeneous staining pattern. No IrCRH was observed in the normal thyroid parenchyma. Using a specific radioimmunoassay, the IrCRH in extracts of simple thyroid goiters, papillary carcinomas, and Hürthle cell tumors ranged between 0.031 and 0.224 pmol/g of wet tissue but was undetectable in normal thyroid parenchyma. The IrCRH molecule in the thyroid gland eluted at the same fraction as synthetic rat/human CRH 1-41 in reverse phase high pressure liquid chromatography. We conclude that IrCRH is present in thyroid lesions, predominantly in those related to autoimmune phenomena, suggesting that this neuropeptide may be directly and/or indirectly involved with inflammatory processes taking place in this gland.     

Laboratory based study of undetectable thyroid stimulating hormone.

The clinical importance of an undetectable thyroid stimulating hormone (TSH) concentration (less than 0.2 mU/l) was studied in a consecutive series of 2573 requests for routine thyroid function tests. Two hundred and seventeen (8.4%) patients had an undetectable TSH concentration, and of these 39 (18%) had otherwise normal thyroid hormone concentrations and no history of thyroid disease. In a follow up study 71 patients (34 outpatients and 37 inpatients) with undetectable TSH concentration associated with otherwise normal thyroid hormone concentrations were randomly selected during routine reporting of thyroid function test results. None of these patients had a history of thyroid disease. Sex hormone binding globulin concentrations were increased in five out of 50 of these patients and antithyroid antibodies were detectable in four out of 49, suggesting that in most cases the isolated undetectable TSH concentration was not associated with thyroid dysfunction, particularly hyperthyroidism. Isolated undetectable TSH concentration was observed in both inpatients and outpatients and was not associated with any particular clinical condition. Repeat specimens were received in 54 of the 71 patients and TSH concentration remained persistently undetectable in 35 of these.     

Immune function of thyroid stimulating hormone and receptor

Thyroid stimulating hormone (TSH) is a central component of the hypothalamus-pituitary-thyroid axis. Although TSH is known for its important biological effects as a neuroendocrine used to regulate thyroid hormone activity and subsequent metabolic functions, TSH also has been shown to be produced and used by cells ofthe mammalian immune system. Moreover, recent findings have linked the use of TSH by cells of the immune system in humans and mice to a group of monocytic cells and lymphocytes--primarily dendritic cells, macrophages, and subset of na?ve peripheral T cells. Other studies have demonstrated the capacity of dendritic cells and monocytes to produce biologically active TSH, thereby pointing to a process of paracrine or autocrine TSH-mediated communication during the earliest stages of an immune response to antigen. In this article, these and other features of TSH immune-endocrine interactions are discussed in the context of an intrinsic TSH immunological pathway. Additionally, a hypothesis is proposed in which TSH produced by cells of the immune system during acute antigen exposure plays a dual role, consisting on the one hand of TSH communication during antigen-driven immune activation while concomitantly serving to regulate physiological homeostasis by modulating and adjusting thyroid hormone activity.     

Molecular basis for the autoreactivity against thyroid stimulating hormone receptor.

The present report identifies an important immunogenic region of the TSH receptor and determinants on the TSH receptor for the two types of autoantibodies seen in hyperthyroid Graves' disease and hypothyroid idiopathic myxedema, TSAbs and TSBAbs, respectively. The immunogenic domain with no important functional determinants, is contained within residues 303-382 and involves residues 352-366 in particular. There are determinants flanking the immunogenic domain on the C-terminal portion of the receptor which are the TSBAb and high affinity TSH binding sites: residues 295-306, 387-395, and tyrosine 385. Determinants on the N-terminal portion of the external domain, centered on residues 38-45, are TSAb interactions linked to low affinity TSH binding important for signal generation: threonine 40 and residues 30-33, 34-37, 42-45, 52-56, and 58-61. These determinants are conserved in human and rat receptors, are not present in gonadotropin receptors, and are each related to separate actions of TSH: binding vs. signal generation. They can, therefore, account for organ specific autoimmunity and the different disease expression effected by TSBAbs vs TSAbs, i.e. hypo- vs. hyperthyroidism, respectively. It is proposed that, in the thyroid, hormonal (TSH, insulin, hydrocortisone, IGF-I) suppression of class I genes might be one means of preserving self-tolerance in the face of the hormone action to increase the expression of tissue specific genes such as thyroglobulin and thyroid peroxidase. Inappropriately high class I expression in the thyroid, i.e. if induced by interferon, viruses, or some as yet unknown agent, would contribute to the generation of autoimmune disease. Thus, it would result in increased antigen presentation to the immune system, particularly those autoantigens increased by TSH and its cAMP signal such as thyroglobulin or thyroid peroxidase, or whose turnover is increased by TSH and its cAMP signal, such as the TSH receptor. In the case of the latter, peptide 352-366, known to be near a protease sensitive site on the receptor [41,49], would now act as a potent self-antigen and induce the formation of receptor autoantibodies. It is further proposed that methimazole and high doses of iodide are therapeutically effective agents in thyroid autoimmune disease because they, in part, decrease MHC class I gene expression. Speculation is presented which suggests that elimination of negative regulation of MHC class I and the TSH receptor is an important factor in the development of autoimmune thyroid disease.(ABSTRACT TRUNCATED AT 400 WORDS)     

Thyroid antoantibodies and the response to thyrotropin releasing hormone in patients with subclinical hypothyroidism.

AIM--To evaluate the clinical usefulness of the thyrotropin releasing hormone (TRH) test and estimation of thyroid autoantibody concentrations in patients with borderline raised thyroid stimulating hormone (TSH). METHODS--The records of 34 consecutive patients with persistent borderline increased TSH (4.4-9.9 mU/l) referred to the Medical Investigation Unit were reviewed. The response of patients with thyroid autoantibodies to the TRH test was compared with that of patients with a negative antibody screen. RESULTS--Eleven (44%) of 25 patients with positive anti-thyroid microsomal and/or thyroglobulin antibody tests and three (33%) of nine patients with a negative antibody screen had hypothyroid responses to TRH. Neither age nor sex affected the response to TRH. Basal TSH alone was poorly correlated with these indices. Twelve (35%) patients who had elevated basal TSH had a normal response to the TRH test. CONCLUSION--Patients with positive or negative thyroid autoantibodies and an exaggerated response to the TRH test should be regarded as hypothyroid and treated with thyroxine. Patients with positive thyroid autoantibodies and normal TSH response may subsequently develop hypothyroidism and should be given long term follow up.     

Blunted prolactin response to exogenous luteinizing hormone releasing hormone in superovulated women

To investigate the prolactin (PRL) response to luteinizing hormone releasing hormone (LHRH) in superovulated cycles, eight normally ovulating women were studied in two cycles, i.e. a spontaneous (control) and a cycle treated with 'pure' follicle stimulating hormone (FSH) (225 IU/day). LHRH was given to the women i.v. (a single injection of 100 micrograms) in the late follicular phase of both cycles. The oestradiol levels (mean +/- SEM) at the time of the LHRH challenge were 635 +/- 31 and 1707 +/- 225 pmol/l respectively (P less than 0.001). The size of the leading follicle was similar in both cycles. Basal PRL levels (mean +/- SEM) on the day of the LHRH experiment were significantly higher in the FSH (250 +/- 31 microIU/ml) than in the spontaneous cycles (133 +/- 15 microIU/ml. P less than 0.05). In the latter cycles, LHRH induced a significant increase in serum PRL and LH levels, while the FSH cycles, the prolactin (PRL) response to LHRH was blunted and LH response markedly attenuated. We conclude that superovulation induction stimulates basal but suppresses LHRH-induced PRL release. It is suggested that basal PRL secretion is LHRH-independent and the suppressing effect is mediated via previously described paracrine interactions between the gonadotrophs and lactotrophs and/or through ovarian inhibitory substances.     

Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress

The skin is a known target organ for the proopiomelanocortin (POMC)-derived neuropeptides alpha-melanocyte stimulating hormone (alpha-MSH), beta-endorphin, and ACTH and also a source of these peptides. Skin expression levels of the POMC gene and POMC/corticotropin releasing hormone (CRH) peptides are not static but are determined by such factors as the physiological changes associated with hair cycle (highest in anagen phase), ultraviolet radiation (UVR) exposure, immune cytokine release, or the presence of cutaneous pathology. Among the cytokines, the proinflammatory interleukin-1 produces important upregulation of cutaneous levels of POMC mRNA, POMC peptides, and MSH receptors; UVR also stimulates expression of all the components of the CRH/POMC system including expression of the corresponding receptors. Molecular characterization of the cutaneous POMC gene shows mRNA forms similar to those found in the pituitary, which are expressed together with shorter variants. The receptors for POMC peptides expressed in the skin are functional and include MC1, MC5 and mu-opiate, although most predominant are those of the MC1 class recognizing MSH and ACTH. Receptors for CRH are also present in the skin. Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses. The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis. Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis. This CRH/POMC skin system appears to generate a function analogous to the HPA axis, that in the skin is expressed as a highly localized response which neutralizes noxious stimuli and attendant immune reactions.