Gender and age influence the relationship between serum GH and IGF-I in patients with acromegaly

BACKGROUND: In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30-50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. OBJECTIVE: To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. METHODS: Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24-81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. RESULTS: The median calculated GH value was 4.7 mU/l (range 1-104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0.5, P < 0.0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF-I was observed for males and females. On average, women had serum IGF-I levels 11.44 nmol/l lower than men with the same mean serum GH (P = 0.03, 95% CI 1.33-21.4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF-I was estimated to fall by 0.37 nmol/l per year (P = 0.04, 95% CI 0.015-0.72). CONCLUSIONS: In keeping with previous observations of relative GH resistance in normal and GH-deficient females we have observed lower serum IGF-I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender-dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF-I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF-I and GH as markers of disease activity in acromegaly.     

TSH response to TRH in euthyroid insulin-dependent diabetics

Summary In order to establish the exact profile of thyroid function in Insulin Dependent Diabetics (IDD), we have measured T4, T3 basal and TRH stimulated TSH concentrations in 22 IDD. Four patients with positive thyroid antibodies showed increased basal and TRH stimulated TSH concentrations; this situation may be indicative of subclinical hypothyroidism.     

The relationship between serum GH and serum IGF-I in acromegaly is gender-specific.

In patients with acromegaly, there is a linear association between log10 serum GH and IGF-I. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and in adult GH deficiency, the dose of exogenous GH required to achieve a given serum IGF-I is significantly greater in females than males. We report the influence of gender on the relationship between serum GH and IGF-I in subjects with active acromegaly. A single, fasted, serum sample was obtained from 153 subjects with active disease (87 males; median age, 47.8 yr; range, 20-82 yr) in whom serum IGF-I was at least 30% above the upper limit of an age-related reference range after washout from medical therapy. A linear correlation between serum IGF-I and log10 serum GH was observed (r = 0.53; P < 0.0001), but this relationship was significantly influenced by gender. For a given serum GH value, females were estimated to have serum IGF-I values 82 ng/ml less than males [P < 0.02; 95% confidence interval (CI), 15.2-149]. In females receiving oral E, mean serum IGF-I for a given GH value was 130 ng/ml lower than in males (P = 0.01; 95% CI, 29.8-230.2) but only 60 ng/ml less than the remaining 45 females (NS; P = 0.2). This study demonstrates a gender difference in the relationship between serum GH and IGF-I in patients with active acromegaly consistent with relative GH resistance observed in normal and GHD females, which may, in part, be mediated by E. This observation has important implications for the use of IGF-I as a measure of disease activity.     

Decreased TSH response to TRH induced by amiodarone

In order to test the reactivity of TSH to TRH during amiodarone treatment we investigated 7 hypothyroid subjects treated with 50 micrograms T3/day. A TRH test (200 micrograms iv) was performed before and after 6 weeks of treatment with 400 mg amiodarone/day. Amiodarone treatment induced a significant increase in serum total and free T3 (from 2.17 +/- 0.13 to 3.55 +/- 0.58 nmol/l and from 5.6 +/- 0.61 to 9.46 +/- 1.41 pmol/l). Basal TSH levels were significantly decreased and the maximal stimulation of TSH 20 min after TRH injection was only 20.0 +/- 3.3 mU/l during amiodarone treatment compared with 61.4 +/- 10.4 mU/l before treatment. These results indicate that in hypothyroid patients treated with amiodarone, the TSH response to TRH is blunted and that this is likely to be related to the higher total and free T3 levels or to a direct effect of amiodarone at the pituitary level.     

TSH response to TRH in euthyroid,hypercholesterolemic patients treated with graded doses of dextrothyroxine

In an attempt to determine the minimum dose of D-Thyroxine (D-T₄) which will suppress pituitary TSH response to TRH, we have treated 6 euthyroid, hypercholesterolemic patients with graded doses of D-T₄. TSH response was suppressed in 3 patients with 3 mg and in the remaining 3 patients with 4 mg D-T₄ administered once daily. The mean TSH suppressive dose of 3.5 mg, as determined in this study, is considerably less than the 6 mg daily dose given to patients treated with D-T₄ in the Coronary Drug Project. This suggests that the adverse effects observed with D-T₄ treatment in the Coronary Drug Project may have been due to mild, undetected hyperthyroidism. D-T₄ treatment in our patients was not associated with an increase in heart rate or ventricular ectopic beats as determined by Holter monitoring. However, bile samples obtained at the time of TSH suppression showed a significant increase in lithogenic index. In four patients, TSH suppressive doses of D-T₄ were associated with a 12% decrease in mean cholesterol and a 17% decrease in mean LDL cholesterol concentrations.     

Enhanced hypothalamic dopaminergic inhibition of LH, TSH and GH release in patients with pathological hyperprolactinaemia

Recent studies have suggested that patients with prolactinomas have a defect in the central regulation of prolactin (Prl) release but it is not clear whether the defect results from a true loss of hypothalamic dopamine activity or from a functional inability of inherent dopaminergic inhibition to be mediated effectively. We have studied this question by the use of monoiodtyrosine (MIT, 1 g orally), a specific inhibitor of central dopamine synthesis to remove dopaminergic inhibitory control of Prl release in 10 normal ovulating women, 8 women on oral contraceptive steroids (OC) and 8 patients with pathological hyperprolactinaemia (PHP). LH, TSH and GH were also measured during the study in view of recent reports suggesting that dopaminergic mechanisms may be involved in modulating their secretion. Subjects on OC had a significantly higher (P less than 0.05) mean basal Prl (353 +/- 34 vs 280 +/- 26 mIU/l) and a significantly greater (P less than 0.05) peak response (incremental change 2270 +/- 300 mIU/l to MIT than normal controls (1320 +/- 220 mIU/l). Patients with PHP had a highly significantly blunted (P less than 0.001). Prl response (incremental chane 290 +/- 95 mIU/l) compared to controls. MIT administration caused a significant increase in LH (P less than 0.05), TSH (P less than 0.01) and GH (P less than 0.01) in patients with PHP but not in normal or OC-treated subjects. The augmented Prl response of subjects on OC is consistent with an increase in dopaminergic inhibitory control of Prl release. The lack of Prl response in subjects with PHP is indicative of a functional loss of dopaminergic control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early postoperative basal serum GH level and the GH response to TRH in relation to the long-term outcome of surgical treatment for acromegaly: a report on 39 patients

During a 10-year period 39 patients with acromegaly, aged 23-73 years, underwent selective adenomectomy via a trans-sphenoidal or transfrontal (one case) approach. Six to 12 months after the operation, the serum level of growth hormone (GH) was reduced to less than 5 micrograms l-1 in 28 patients (74%) in at least two of three random samples and/or suppressed to less than 3 micrograms l-1 during an oral glucose load, thus fulfilling the commonly used criteria for a successful operation. In 10 patients these criteria for adequate GH reduction were not fulfilled, but their median S-GH level was reduced from 38 to 11 micrograms l-1 (P less than 0.01) after the operation. Surgery was successful in 11 of 13 (85%) patients with a microadenoma (less than 10 mm in diameter), in 10 of 14 (71%) patients with an adenoma of diameter greater than 10 mm but still enclosed in the sella, and in seven of 11 (64%) patients with locally invasive tumours. Impaired pituitary function was observed in 23% of the patients after surgery, independent of tumour size. In one patient the postoperative period was complicated by a lethal intracranial infection. During follow-up for 1-10 years, four patients relapsed, after 1, 1.5, 6 and 9 years, respectively. Patients for whom surgery appeared to have been ineffective at the evaluation 6-12 months postoperatively, or who later relapsed were identified by early (within 7 d) postoperative serum GH with a sensitivity of 90%. The accuracy for identification of a satisfactory outcome of surgery was 85%, and the predictive value was 90%. The corresponding values for the GH response to TRH measured 6-12 months postoperatively were 47, 40 and 54%, respectively. It is concluded that the basal level of serum GH measured 1-7 d postoperatively has higher sensitivity and specificity than the GH response to TRH 6-12 months postoperatively for evaluation of the effect of surgery on GH overproduction, and that it has a higher predictive power with regard to the long-term outcome of surgery for acromegaly.     

The effect of iodized oil on the TSH response to TRH in endemic goiter patients.

The TSH and T3 response to synthetic TRH was evaluated in 4 groups of patients: normal controls and goitrous subjects from the urban area of Sao Paulo (urinary iodine excretion: 172.2 +/- 48.3 mug I/g creatinine) and nongoitrous and goitrous subjects from the endemic areas of Sao Bento (urinary iodine excretion: 53.8 +/- 17.1 mug I/g). Plasma T4 and T3 were within our normal range in all groups of patients. The mean plasma TSH was significantly higher (5.2 +/- 3.3 muU/ml) in goitrous subjects living in Sao Bento as compared to normal control groups both in urban or endemic areas, and after TRH these patients had an exaggerated and sustained TSH response with a significantly higher peak level (21.1 +/- 7.9 muU/ml). T3 concentration rose in all subjects following TRH and all patients from the Sao Bento endemic areas had a significantly higher proportionate increase in plasma T3 at 120 min. After an injection of iodized oil basal plasma TSH returned to the normal range in the goitrous subjects from Sao Bento. The mean peak TSH response to TRH was 9.1 +/- 3.8 muU/ml at 3 months after the iodized oil injection, and only at 6 months after the iodized oil TSH response was significantly reduced (peak level: 6.1 +/- 2.4 muU/ml). It is confirmed that plasma TSH levels are increased in endemic goitrous patients but not in normal controls living in the same endemic area and it is suggested that the pituitary threshold for inhibition of secretion of TSH by T4 and T3 has been reset in these goitrous subjects to achieve a persistently higher secretion rate of TSH.     

Paradoxical GH response to TRH during status epilepticus in man

Information on GH in relation to epilepsy is sparse, and to our knowledge there is no information on GH levels during status epilepticus in man. We studied GH in serum in six patients during status epilepticus, and in a control group of six seizure-free patients with epilepsy, before and after injection of TRH. The baseline GH values before TRH administration were within the normal range in all patients. After injection of TRH all patients with status epilepticus showed a paradoxical peak-shaped increase of GH to at least twice their baseline levels within 45 min after the injection (median basal GH value 1.5 mU/l and median peak GH value 6. 5 mU/l, mean increase 330%). No uniform reaction to TRH was observed in the control group (median basal GH value 2.7 U/l and median of the highest value within 45 min 5.2mU/l). A paradoxical peak reaction of GH to TRH was significantly more frequent in the status epilepticus group compared with the control group (P=0.008, Fisher exact probability test). TRH is not considered a GH-releasing hormone in humans during normal conditions, but a paradoxical response of GH to TRH, similar to that observed during status epilepticus, has been reported in various other pathological conditions, such as acromegaly, liver cirrhosis, mental depression and hypothyroidism. Our results of GH release after TRH administration in patients with status epilepticus suggest an altered regulation of GH as a result of the long-standing epileptic activity.     

Heterogeneity of prolactin and TSH response to TRH in hypotonadotropic hypogonadism.

To evaluate prolactin and TSH secretion in isolated gonadotropin deficiency, thyrotropin-releasing hormone (TRH), in a dose of 500 microgram, was administered iv to fifteen male subjects with this disorder. In 4 out of 8 untreated patients, TRH-mediated prolactin release was significantly blunted and this attenuated response was not improved in one patient after treatment with testosterone for 1 year. In 7 patients who were treated with testosterone for 2 to 8 years, four failed to show a normal prolactin response after TRH injection. TRH-induced TSH secretion, on the other hand, was attenuated in two out of 8 untreated and in two of 8 treated patients with hypogonadotropic hypogonadism. The decreased TSH reserve was not necessarily associated with the poor prolactin response to TRH. It was concluded that heterogeneity exists in TRH-mediated prolactin and TSH release in "isolated" gonadotropin deficiency syndrome.     

The growth hormone responses to L-dopa and TRH in acromegaly

The GH responses to TRH and L-dopa were investigated in 14 Indian and African patients with untreated acromegaly. A positive response to L-dopa (greater than 50% change from basal) was obtained in 6 of the 14 patients tested while a positive response to TRH (greater than 100% change from basal) was found in 5 of 12 patients tested. While 9 patients responded to at least one agent, only 2 had a positive response to both agents. Positive responders appeared to be hyper-prolactinemic and have evidence of abnormal glucose tolerance as compared to nonresponders.     

The relation between pituitary magnetic resonance imaging findings and GH, TSH, PRL dynamics in patients with idiopathic GH deficiency

The relation between pituitary magnetic resonance imaging (MRI) findings and anterior pituitary function was studied in 36 patients with classic idiopathic GH deficiency. These patients were divided into three groups based on MRI findings which were compared with those of 14 normal short children; i.e. normal stalk (N = 6), narrowed stalk (N = 20), and transected stalk (N = 10). The transected and narrowed stalk groups showed significantly delayed TSH responses to TRH compared with the normal stalk group and with the normal short children. Further, the mean maximal TSH increment in the narrowed and transected stalk group was slightly greater than that in normal short children. In contrast, there were no differences in basal plasma GH and PRL levels and their responses to GHRH and TRH among the three groups. When the patients were divided into normal anterior pituitary and atrophic pituitary groups regardless of stalk changes or when they were divided into groups of stalk changes (narrowing and transection) with and without pituitary atrophy, no differences in GH, TSH and PRL dynamics between the groups were observed. These results indicate that pituitary thyrotrope functions, but not somatotrope and lactotrope functions, in patients with idiopathic GH deficiency are more closely correlated to stalk changes than to anterior pituitary changes observed on MRI.     

Serum free thyroid hormones and response of TSH to TRH in nonthyroidal illnesses

The change in the levels of free thyroid hormones and the pathophysiology of the hypothalamo-pituitary-thyroid axis of patients with nonthyroidal illness (NTI) have not been clearly elucidated so far. Therefore, it was thought of interest to investigate this problem by determining free thyroid hormones and TSH in serum and the response of TSH to TRH in these patients. The subjects employed in this study were 71 cases with hemodialysis, 40 cases with diabetes mellitus, 24 cases with liver cirrhosis, 12 cases with various cancers, 10 cases with anorexia nervosa and 110 normal subjects as controls. The serum total protein, albumin, free T4, free T3, TSH and other parameters of thyroid function were determined, and the TRH test was performed on about 10 patients of each group. Serum TSH was not only determined by a conventional assay system, but with a highly sensitive method, and the data were compared with one another. It was found that the serum free T3 levels were significantly low in all the groups investigated, but the serum free T4 levels were significantly low only in the groups with hemodialysis, decompensated liver cirrhosis, cancers and anorexia nervosa. No significant lowering of serum free T4 was observed in the patients with diabetes mellitus, acute hepatitis and compensated liver cirrhosis. However, serum TSH levels tended to be higher in all the groups studied, though they were not significant. The response of TSH to TRH was low or delayed in about 20-50% of patients with hemodialysis, diabetes mellitus, liver cirrhosis, cancers and anorexia nervosa. It was observed that the serum rT3 concentration was significantly high in the patients with diabetes mellitus and anorexia nervosa but significantly low in the patients on hemodialysis. In the rest of the groups, there were found many cases who showed high levels of serum rT3 although they were not statistically significant. These results indicate that low concentrations of serum free T3 observed in the majority of the patients with severe NTI were, at least in part, due to the decrease in the peripheral conversion of T4 to T3 and the lowered sensitivity of the anterior pituitary to thyroid hormones and TRH.     

Suppression of the TSH response to TRH by thyroxine therapy in differentiated thyroid carcinoma patients.

Absent response of serum thyrotrophin (TSH) after stimulation with 200 micrograms synthetic thyrotrophin-releasing hormone (TRH) was used as a criterion of adequate suppression of TSH in the treatment of thyroid carcinoma patients with thyroxine. The mean causing total suppression of the response was 223 micrograms of thyroxine per day. At this dose level about 40% of the patients had serum thyroxine concentrations above the upper reference interval and only 10% had elevated triiodothyronine concentrations. In some patients the TSH response to TRH varied between absent and low normal when tested at long intervals. The ideal dose of thyroxine is obviously slightly higher than the smallest one causing total suppression of the TSH response to TRH, i.e. about 250 micrograms a day. The individual dose must be found using the TRH stimulation test because serum thyroid hormone levels cannot be used as a guideline for adequate dosage. In some patients the thyroid remnant of apparently normal thyroid tissue was not totally suppressed although the thyroxine dose was definitely above the level causing suppression of the response to TRH.     

神经型地方性克汀病患者TSH对TRH应答性的研究

本文应用 TRH 兴奋试验来了解地方性神经型克汀病患者下丘脑—垂体—甲状腺轴的功能状态和垂体 TSH 的储备功能。通过对37例分别来自未补碘和已补碘地区的神经型克汀病的研究,认为神经型克汀病与甲低症关系密切,不仅有原发性甲低,而且还有继发性甲低,部分患者垂体 TSH 储备功能较差,同时补碘可改善一部分患者甲状腺功能状态。     

The pituitary TSH response to TRH is inversely related to the plasma TSH concentration and directly related to the pituitary TSH content during hypothyroidism in the rat

We studied the effects of degree and duration of hypothyroidism on the pituitary TSH concentration and the pituitary TSH secretory response to TRH. Varying degrees of hypothyroidism were achieved in thyroparathyroidectomized rats (THYREX) by continuous sc infusion of T3 (0.2, 0.3, 0.4, or 0.5 microgram/100 g X day) or T4 (0.6, 1.2, or 1.8 microgram/100 g X day). While T3 was more potent than T4, both resulted in a dose-dependent suppression of the post-thyroidectomy rise in TSH. After 7 or 14 days of severe hypothyroidism (nonreplaced THYREX rats) the pituitary TSH secretory response to TRH (250 ng/100 g body weight, iv) was found to be decreased when compared to that of euthyroid rats. Decreasing the degree of hypothyroidism increased the pituitary secretory response to TRH and the pituitary TSH content. The results indicate that in the hypothyroid rat: severe hypothyroidism results in a blunted pituitary TSH response to TRH through 14 days after thyroidectomy, at 7 and 14 days after thyroidectomy the pituitary TSH response to exogenous TRH is inversely related to the basal plasma TSH concentration, the pituitary TSH concentration increases with the duration of hypothyroidism, the pituitary TSH content is increased by low rates of thyroid hormone replacement, and the pituitary TSH response to exogenous TRH is directly related to the pituitary TSH content.