GROWTH HORMONE RESPONSES TO GRF 1–29 IN PATIENTS WITH PRIMARY HYPOTHYROIDISM BEFORE AND DURING REPLACEMENT THERAPY WITH THYROXINE

It is well known that hypothyroidism is frequently associated with impaired GH responses to different stimuli. In the present study we have evaluated GH responses to GH-releasing factor (GRF) in patients with primary hypothyroidism before and during T4 replacement therapy. Fourteen patients (age range 26-60 years) underwent two GRF tests (1 microgram/kg) before and during replacement therapy (150 micrograms/d). Administration of T4 increased peak GH responses to GRF in 9 patients and in the group as a whole (mean +/- SEM, 17.0 +/- 2.8 vs 32.6 +/- 5.7 mU/l, P less than 0.02). When the data are analysed by means of area under the curve (AUC), the GH response to GRF was increased by T4 in 10 patients and in the group as a whole (mean +/- SEM, 51.7 +/- 14.3 vs 101.5 +/- 28.1, P less than 0.02). These data indicate that thyroid hormone replacement therapy enhances the responsiveness of the somatotroph to GRF 1-29 in patients with primary hypothyroidism.     

TSH RESPONSES TO TEMPERATURE IN PRIMARY HYPOTHYROIDISM

We have studied the serum TSH responses to alterations in body temperature by heating twelve patients with primary hypothyroidism for 48 h and determining the initial and final TSH levels. In four control patients, we estimated the TSH responses to rest and exercise. In a group of three patients, the TSH levels were recorded at frequent intervals over a 48 h period, during which they were rested and subsequently warmed. Our results show that in the twelve patients initially investigated, there was a significant fall in TSH. In the smaller group of three patients studied more intensively, TSH levels were inversely related to cutaneous and core temperature. In primary hypothyroidism alterations in body temperature influence the levels of circulating TSH.     

END-ORGAN RESPONSES TO THYROXINE THERAPY IN SUBCLINICAL HYPOTHYROIDISM

We studied variables known to change with thyroid hormone status in 18 patients with subclinical hypothyroidism before and during treatment with thyroxine in a dose sufficient to restore the plasma TSH response to TRH to normal. There was an associated increase in both plasma total T4 and free T4 within the normal range but plasma total T3 and free T3 were unchanged. As a result of thyroxine treatment there was a small but significant increase (P less than 0.05) in left ventricular ejection fraction (LVEF) with maximal exercise but no significant changes in LVEF at rest and moderate exercise, continuously monitored mean sleeping heart rate, day/night ratios of urinary sodium excretion, peripheral nerve conduction velocities, fasting serum triglycerides, total cholesterol (TC), high density lipoproteins (HDL) or TC/HDL ratios. On this evidence we do not consider that thyroxine replacement therapy is indicated in patients with subclinical hypothyroidism.     

COMPUTED TOMOGRAPHY OF THE PITUITARY FOSSA IN PRIMARY HYPOTHYROIDISM. EFFECT OF THYROXINE TREATMENT

Computed tomography of the pituitary fossa was performed in 12 patients with primary hypothyroidism before and after thyroxine treatment. In three, herniation of the diaphragma sellae precluded accurate measurement of the density of the hypophysis. Eight of the remaining patients showed abnormally increased density of the pituitary gland after intravenous injection of contrast substance which was significantly correlated with the serum TSH-level (r = 0.913, P less than 0.001). After thyroxine treatment the intrasellar density decreased substantially in all but one. We suggest that the observed contrast enhancement reflects increased pituitary circulation associated with the augmented function of TSH-producing cells in response to thyroid hormone deficiency.     

BROMOCRIPTINE TREATMENT OF SEVEN WOMEN WITH PRIMARY AMENORRHOEA AND PROLACTIN-SECRETING PITUITARY TUMOURS

Seven women with primary amenorrhoea and hyperprolactinaemia were treated with bromocriptine. All the women had started to develop secondary sex characteristics at normal age but pubertal development stopped and menarche did not occur. Radiological signs of a pituitary tumour were found in all the women. Before the pituitary tumour was diagnosed, four women had been given longterm cyclical oestrogen replacement therapy. Three women had received primary tumour therapy with surgery and/or irradiation but had persistent hyperprolactinaemia. The basal luteinizing hormone (LH) levels were low in four of the women while all the women had normal basal levels of follicle-stimulating hormone (FSH) and normal or exaggerated gonadotrophin responses to luteinizing hormone-releasing hormone (LHRH). None of the women had evidence of endogenous oestrogen production before treatment. Bromocriptine treatment normalized the raised serum prolactin levels (46-2900 microgram/l) in all but one woman, in whom the prolactin level decreased from 160 to 38 microgram/l. Regular ovulatory menstrual cycles appeared in four women, one of whom had previously been treated by transsphenoidal adenomectomy followed by external irradiation. Two other women with persistent hyperprolactinaemia after previous surgical and/or irradiation treatment of large pituitary tumours did not menstruate after more than one year of treatment with bromocriptine. One infertile patient with a microadenoma conceived at the first ovulation on therapy and developed symptoms and signs of tumour growth during pregnancy.     

CORTICOTROPHIN RELEASING FACTOR: RESPONSES IN NORMAL SUBJECTS AND PATIENTS WITH DISORDERS OF THE HYPOTHALAMUS AND PITUITARY

Synthetic CRF-41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (± SE) was 276 ± 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r= -0·56; P<0·02). The mean peak serum cortisol was 662 ± 34 nmol/1 and the mean peak corticosterone was 28·6 ± 3·8 nmol/1. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r= 0·84; P<0·0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF-41. The peak serum cortisol following CRF-41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin-induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 μg of CRF-41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF-41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary-dependent Cushing's disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF-41. These normal or enhanced responses of hypercortisolaemic patients with Cushing's syndrome contrast with the complete inhibition of the responses to CRF-41 in normal subjects given dexamethasone. In the treated patients with Cushing's syndrome     

PRIMARY HYPOTHYROIDISM AND ESSENTIAL HYPERNATREMIA IN A PATIENT WITH HISTIOCYTOSIS X

Abstract: :A 27 year old woman with histiocytosis X had an unusual initial presentation with features of primary hypothyroidism and a goitre. Diagnosis was made by lung and thyroid biopsies. Endocrine tests showed the presence of hypopituitarism and a discrete suprasellar mass, consistent with hypothalamic histiocytosis X, was demonstrated by computerised tomography. Radiotherapy and chemotherapy arrested the clinical progression of the disease.     

AUGMENTATION OF PITUITARY THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE DURING SUBPHYSIOLOGICAL TRI-IODOTHYROININE THERAPY IN HYPOTHYROIDISM

Five hypothyroid patients are reported with increased pituitary TSH response to TRH during administration of T3. In one patient treated with intravenous T3, 50 micrograms daily for 10 days, the peak serum TSH and total pituitary TSH reserve after TRH increased coincident with increases in serum T3 and T4 levels and a decrease in the basal TSH concentration. In four patients treated with oral T3, the peak serum TSH and total pituitary TSH reserve after TRH increased during administration of subphysiological doses of T3. Peak serum T3 levels occurred 4 h after ingestion and increased progressively with increasing T3 doses. Serum TSH levels decreased modestly with the nadir at 4 h after T3 ingestion and then returned to basal levels at 24 h. Augmentation of TSH responses to TRH occurred simultaneously with decreases in serum cholesterol, as well as increases in the pituitary prolactin response to TRH, and increase in the GH and cortisol response to insulin induced hypoglycaemia where these responses could be studied. These data demonstrated a positive effect of subphysiological T3 therapy in these hypothyroid patients on the TSH response to TRH as well as increases in the responses of other pituitary hormones to stimulation.     

PRIMARY HYPOTHYROIDISM WITH GROSSLY ELEVATED PLASMA TOTAL THYROXINE AND TRIIODOTHYRONINE LEVELS

In an elderly patient with clinical primary hypothyroidism and a raised basal TSH, the serum free thyroxine (fT4), total thyroxine (TT4) and triiodothyronine (TT3) were consistently and paradoxically grossly elevated when measured by radioimmunoassay. In part these hormone levels were due to a high titre of endogenous IgG immunoglobulins which bound T4, T3 and reverse T3 (rT3) and thus caused gross interference in the radioimmunoassays. However, when this methodological interference was removed by using a methanolic extract of the patient's serum, the concentrations of TT4 and TT3 were still grossly elevated. It was only when basal TSH and the concentration of fT4 and fT3 were measured by equilibrium dialysis that these hormone levels were found to be consistent with primary hypothyroidism.     

HYPERPROLACTINAEMIA AND MICROADENOMAS IN PRIMARY HYPOTHYROIDISM

The presence at presentation of hyperprolactinaemia and abnormalities on high resolution computed tomographic (CT) scanning of the pituitary gland have been documented in 19 patients with primary hypothyroidism. The changes on thyroid hormone replacement were followed for up to 28 months after presentation. At presentation serum PRL was elevated in 12 subjects (454 to 2612 mU/l); after stabilization of thyroid replacement PRL remained raised in 9 patients (525 to 1888 mU/l) despite 10-18 months of treatment. Pretreatment CT scans showed enlarged pituitaries in 11 patients with suprasellar extension in five. In 11 patients there was initially an area of low attenuation suggesting a microadenoma and on rescanning this appearance remained in five patients. Hyperprolactinaemia in hypothyroid patients does not always return to normal with thyroid hormone replacement.     

FAMILIAL HYPERCHOLESTEROLAEMIA AND PRIMARY HYPOTHYROIDISM: COEXISTENCE OF BOTH DISORDERS IN A YOUNG WOMAN WITH SEVERE HYPERCHOLESTEROLAEMIA

Severe hypercholesterolaemia in a 17-year-old girl was found to be due to the coexistence of heterozygous familial hypercholesterolaemia and chronic lymphocytic thyroiditis with primary hypothyroidism. Her cultured skin fibroblasts showed a 70–75% reduction in the binding, internalization and degradation of ¹²⁵I-labelled low density lipoprotein and several other family members were hypercholesterolaemic. Replacement therapy with L-thyroxine reduced the concentrations of total and low density lipoprotein cholesterol and apoprotein B in the patient's plasma to values similar to those in other sibs with only heterozygous familial hypercholesterolaemia. Severe hypercholesterolaemia attributable to coexistent heterozygous familial hypercholesterolaemia and hypothyroidism in teenage girls may be estimated to occur with a frequency of between 1 in 500 000 and 1 in 10⁶. This value is similar to the gene frequency for homozygous familial hypercholesterolaemia.     

DISCORDANT SERUM α-SUBUNIT AND FSH CONCENTRATIONS IN A WOMAN WITH A PITUITARY TUMOUR

We have studied a women who presented at the age of 51 with a large FSH and alpha-subunit producing pituitary adenoma. Following insertion of ventriculo-peritoneal shunts and external pituitary irradiation there was no change in the elevated serum concentrations of FSH, and alpha-subunit over a four year period although she developed both ACTH and TSH deficiency. Various drugs, however, did alter the FSH and alpha-subunit concentrations and these changes suggest possible mechanisms controlling FSH secretion. Ethinyloestradiol 0.03 mg daily for three weeks suppressed serum FSH to 77% of the basal level (240 +/- 35 i.u./l to 184 +/- 20 i.u./l) but alpha-subunit rose to 130% of basal level (281 +/- 50 ng/ml to 366 +/- 40 ng/ml). On ethinyloestradiol 0.1 mg daily, FSH suppressed to 17% of basal (40 +/- 11 i.u./l) with no change in alpha-subunit concentration, while on 0.2 mg daily suppression of FSH was similar but alpha-subunit fell to 59% of basal (190 +/- 28 ng/ml). Dexamethasone, 3 mg daily for one week reduced FSH to 53% of the initial concentration and alpha-subunit to 74% while bromocriptine 7.5 mg daily for three months, reduced FSH to 39% and alpha-subunit to 66% of basal. Neither thyroxine, 0.2 mg daily for four weeks, nor an LHRH analogue, (Buserelin, Hoechst) 200 micrograms, three times daily for three months elicited any effect. Chromatography on Sephadex G100 showed that serum FSH and alpha-subunit both had Kav values somewhat lower than those of their standard counterparts (FSH, 0.20 vs 0.25; alpha-subunit 0.35 vs 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)     

GONADOTROPHIN, GROWTH HORMONE AND PROLACTIN SECRETION IN CHILDREN WITH PRIMARY HYPOTHYROIDISM

We have studied eight children with primary hypothyroidism (6F, 2M) aged 6.7 to 14.2 years. The girls were prepubertal and the boys had early normal pubertal development. Overnight secretion of LH, FSH, TSH, PRL and GH, and ovarian ultrasound morphology were assessed before and up to 9 months after commencing thyroxine treatment. Serum FSH concentrations in all the girls were increased above LH levels and severe hypothyroidism was associated with reduced GH secretion. These abnormalities reversed with thyroxine treatment. The boys had less severe hypothyroidism and did not demonstrate abnormal gonadotropin or GH secretion. We conclude that primary hypothyroidism in childhood is associated with widespread disturbance of pituitary function, including increased FSH secretion often without signs of early sexual maturation.     

EFFECTS OF PROTRACTED HYPOTHYROIDISM ON PITUITARY FUNCTION AND STRUCTURE IN ENDEMIC CRETINISM

Pituitary function and structure were assessed in 69 endemic cretins from western China. In hypothyroid cretins (TSH greater than 10 mIU/l), CT imaging of the pituitary revealed adenoma in five of 20 (25%) and partially empty sella (PES) in a further eight of 20 (40%). The majority of tumours were microadenomas and showed a relation with higher levels of serum TSH but not with duration of hypothyroidism. Dynamic pituitary testing with TRH and GnRH in four patients with adenoma on CT gave a flat TSH response but significant rises in serum PRL, GH, LH and FSH concentrations. Hyperprolactinaemia (greater than 350 mIU/l) was present in hypothyroid cretins only (13 of 26; 50%) and serum PRL showed a curvilinear relation with serum TSH levels (r = 0.7, P less than 0.0001). Hypogonadism was seen in approximately half the cretins with high PRL levels. Our data suggest that severe protracted thyroid hormone deficiency may result in thyrotrophin adenomas of the pituitary gland. Disturbances of growth, puberty, and sexual function in endemic cretins are explained by the secondary effects of thyroid hormone deficiency on pituitary function.     

METERGOLINE INHIBITION OF THYROTROPHIN AND PROLACTIN SECRETIONS IN PRIMARY HYPOTHYROIDISM

The effect of acute oral administration of metergoline on serum thyrotrophin and prolactin levels in six patients with primary hypothyroidism was studied. Metergoline 4 mg by mouth caused a significant decrease in the concentration of serum thyrotrophin and prolactin in all subjects. There was no consistent change in serum thyroxine and triiodothyronine concentrations during the experiment. These findings suggest that metergoline inhibits prolactin and thyrotrophin secretion by a direct action on the hypothalamus or pituitary gland.     

PERSISTENT TRH-INDUCED GROWTH HORMONE RELEASE AFTER SHORT-TERM AND LONG-TERM L-THYROXINE REPLACEMENT THERAPY IN PRIMARY CONGENITAL HYPOTHYROIDISM

No appreciable changes in plasma GH levels after TRH stimulation have been observed in normal subjects, whereas acute GH release has been reported in primary hypothyroidism and other pathophysiological states. To evaluate the effect of the T4 replacement therapy on TRH-induced GH release, 28 patient volunteers with primary congenital hypothyroidism (PCH), were studied before (11 subjects), after 1 month (nine subjects) and after long-term T4 replacement therapy (eight subjects). All patients underwent a TRH test with measurement of TSH, PRL and GH levels, and were compared to 28 age-matched normal subjects. An increase of plasma GH after TRH was found in 46% of patients without any therapy, in 67% of patients after one month of T4 administration and in 75% of patients after long-term therapy. No changes were observed in plasma GH levels in controls. The TSH response to TRH was inhibited and the response of PRL was reduced step by step by T4 replacement therapy in our patients with PCH. Our results suggest that: (i) Replacement T4 therapy in PCH does not abolish the paradoxical GH response to TRH, in spite of inhibiting the TSH response and reducing the exaggerated PRL response; (ii) the GH response to TRH in PCH seems to be unrelated to low thyroid hormone levels and/or to high TSH levels, but it could be due to changes in hypothalamic-pituitary regulation which are not improved by T4 replacement therapy.     

PRESENCE OF BOTH STIMULATING AND BLOCKING TYPES OF TSH-RECEPTOR ANTIBODIES IN SERA FROM THREE PATIENTS WITH PRIMARY HYPOTHYROIDISM

A case report of three patients with primary hypothyroidism who had potent TSH-binding inhibitor immunoglobulins (TBII) and both thyroid stimulating (TSAb) and thyroid stimulation-blocking antibodies (TSBAb) has been described. Two patients displayed symptoms and signs indistinguishable from those in primary myxoedema (cases 1 and 2), and another patient had a history of Graves' disease (case 3). TBII, TSAb and TSBAb activities were 90.0, 1084.2 and 94.5% in case 1, 91.5, 826.6 and 95.8% in case 2, 76.0, 230.0 and 95.0% in case 3, respectively (normal range, less than 11.0%, less than 145.0 and less than 22.0%, respectively. The results indicate that both stimulating and blocking types of TSH-receptor antibodies exist in these patients. The possible mechanism whereby hypothyroidism developed has been discussed.     

THYROTROPHIN RESPONSES TO INTRAVENOUS THYROTROPHIN-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMIC AND PITUITARY DISEASE

Plasma immunoreactive thyrotrophin (TSH) responses to synthetic thyrotrophin releasing hormone (TRH) have been measured in forty-five patients with pituitary or hypothalamic disease (largely non-functioning and functioning pituitary tumours) tested before and/or after ablative treatment. Subnormal TSH responses usually indicated impaired pituitary function but were less sensitive indices than those of human growth hormone (HGH) after hypoglycaemia. High basal TSH values with exaggerated rises after TRH were occasionally found with hypothyroidism and impaired HGH and cortisol secretion. Delayed TSH responses were indicative of hypothalamic disease in some cases, but in others were associated with pituitary tumours without overt hypothalamic disease. Normal TRH tests were found with hypothyroidism, while five abnormal tests (four delayed) were found in euthyroid patients. Patterns of TSH response to TRH in hypothalamic-pituitary disease are complex and their significance is not always clear.     

DEVELOPMENT OF HYPERTHYROIDISM FOLLOWING PRIMARY HYPOTHYROIDISM: A CASE REPORT WITH CHANGES IN THYROID-RELATED ANTIBODIES

We report a 48-year-old woman who developed hyperthyroidism following primary hypothyroidism. The serum T4 level was initially low and serum TSH level was high with clinical signs of hypothyroidism. The thyroid gland was not enlarged. Therapy with L-T4 was started. Three years later she developed hyperthyroidism; serum free T4 increased to 29.1 pmol/l after cessation of L-T4 therapy. The 123I thyroid uptake was increased with no suppression by exogenous T3. When she was hypothyroid, the activity of thyroid stimulating antibodies (TSAb) in serum measured by cyclic AMP production in cultured porcine thyroid cells were negative at 93.4% (normal less than 140%), while thyroid stimulation-blocking antibodies (TSBAb) determined by inhibition of TSH-induced cyclic AMP increase were positive at 96.1% (normal less than 40%). When hyperthyroidism subsequently occurred, TSBAb became negative (30.9%), while TSBAb became positive (163.3%). The findings indicate that hypothyroidism due to the potent TSBAb activity is not always persistent, but can be changed when various types of thyroid-relating antibodies change in the course of the disease.     

DIFFERENT HEPATIC RESPONSES TO THYROXINE REPLACEMENT IN SPONTANEOUS AND 131I-INDUCED PRIMARY HYPOTHYROIDISM

The serum levels of a range of analytes known to change with thyroid status were measured in two groups of patients with primary hypothyroidism commencing T4 replacement therapy. One group (group 1; n = 9) had spontaneous hypothyroidism whilst in the second (group 2; n = 10), hypothyroidism had resulted from radioiodine therapy. The replacement dose was increased in 50 micrograms increments each month to 200 micrograms/day; this produced similar serum concentrations of thyroid hormones and TSH in the two groups at each dose. Dose-dependent increases in glutathione S-transferase (GST) were seen in both groups but changes in alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) activities occurred only in group 1 patients. Group 1 patients had significantly higher levels of GST than group 2 at the 150 micrograms (P less than 0.01) and the 200 micrograms (P less than 0.005) doses of T4, and they had higher activities of ALT (P less than 0.01) and GGT (P less than 0.02) at the 200 micrograms dose. Seven patients in group 1 had abnormalities in GST and four had high levels of ALT, whereas three patients from group 2 had high GST concentrations and all had ALT activities within reference limits. The concentrations of the other analytes measured in serum showed the same response to T4 in the two groups, particularly the concentrations of certain transport proteins whose serum concentrations depend on hepatic protein synthesis. These data suggest that patients with spontaneous primary hypothyroidism are more susceptible to hepatocellular damage than patients who have radioiodine-induced primary hypothyroidism when given oral doses of thyroxine greater than 150 micrograms/day.