EFFECT OF CIMETIDINE ON SERUM PROLACTIN IN NORMAL WOMEN AND PATIENTS WITH HYPERPROLACTINAEMIA

In normal women, intravenous injection of the H₂-antihistamine, cimetidine, provoked a 3–4 fold rise in serum prolactin, without changes in serum growth hormone, thyrotrophin, or gonadotrophins. Hyperprolactinaemic patients with pituitary tumours, idiopathic hyperprolactinaemia or hypothalamic lesions demonstrated little or no rise in serum prolactin (expressed as a percentage increment) in response to cimetidine; these responses were significantly more blunted than the prolactin responses to intravenous TRH in the same subjects. Post-partum women also demonstrated blunted percentage prolactin responses to cimetidine, although responses to TRH were, in most patients, normal. Dynamic testing of prolactin secretion with cimetidine is no more useful than TRH in distinguishing tumourous from non-tumourous hyperprolactinaemia.     

地方性氟中毒病人血清甲状腺激素与血氟含量关系的探讨

地方性氟中毒为一种全身性疾病。我们观察了37例病人的血清游离氟浓度,甲状腺激素及 TSH 浓度,发现地方性氟中毒病人的血清 T_4及 T_3显著低于正常对照组,TSH 显著高于正常对照组,rT_3与正常对照组无显著性差异,T_3浓度及 T_3/T_4比值与血清游离氟浓度呈显著负相关。提出氟中毒可以降低甲状腺功能,并与血氟含量有关。     

GROWTH HORMONE-RELEASING FACTOR INCREASES SERUM PROLACTIN CONCENTRATIONS IN NORMAL SUBJECTS AND IN PATIENTS WITH PITUITARY ADENOMAS

We have examined the serum growth hormone (GH) and prolactin (PRL) response to growth hormone releasing factor (hGRF-(1-44)NH2 (GRF) 1 microgram/kg i.v. bolus) in 16 acromegalic patients (eight of whom were hyperprolactinaemic), 13 patients with microprolactinoma, and 14 healthy subjects. The GH responses to TRH and to the somatostatin analogue SMS 201-995 were also studied in acromegalic patients. In these, and in patients with microprolactinoma, GH responses after GRF (P less than 0.001 vs saline) were variable. The absolute GH increase (calculated as area under the curve) in acromegalic patients (2489 +/- 920 micrograms/l min), or in patients with microprolactinoma (1322 +/- 279 micrograms/l min) was not different from that in controls (2238 +/- 633 micrograms/l min). In addition, a significant increase in PRL release was observed after GRF in comparison to saline in acromegalic patients (P less than 0.01), in patients with microprolactinoma and in normal subjects (P less than 0.001). The PRL increase was significantly correlated with basal PRL levels in acromegalic patients (r = 0.99, P less than 0.001) and in patients with microprolactinomas (r = 0.61, P less than 0.05). Furthermore, a significant correlation was found between GH rise after GRF and basal GH, and between GH rise after GRF and GH decrement after SMS in patients with acromegaly. These results suggest that GRF can stimulate PRL release by actions on the normal pituitary and on pituitary adenomas, including microprolactinomas. Moreover, the data suggest that in acromegaly there is a relative functional deficiency of hypothalamic somatostatin.     

ANDROSTERONE GLUCURONIDE IS A MARKER OF ADRENAL HYPERANDROGENISM IN HIRSUTE WOMEN

Androsterone glucuronide (Andros-G), a dihydrotestosterone metabolite, is present in serum at concentrations at least tenfold greater than those of androstanediol glucuronide. To investigate the significance of serum androsterone glucuronide, we developed a direct radioimmunoassay for this compound and measured its levels in normal women, women with mild or severe idiopathic hirsutism (IH), hirsute women with polycystic ovarian syndrome (PCO), and non-hirsute obese women. To determine the source of Andros-G precursors, serum levels were measured before and after selective ovarian suppression with leuprolide, combined ovarian and adrenal suppression with leuprolide and dexamethasone, and adrenal stimulation with ACTH. Androsterone glucuronide levels (nmol/l; mean +/- SD) were significantly higher (P less than 0.025) in women with mild idiopathic hirsutism (IH) (185 +/- 91), severe IH (173 +/- 97), and hirsute women with polycystic ovarian syndrome (PCO) (178 +/- 102) than in normal women (110 +/- 26). Levels in non-hirsute obese women (64 +/- 19) were lower than in normal women (P less than 0.01). Baseline levels (mean +/- SEM) in hirsute women given 20 micrograms/kg/day leuprolide for 5-9 months (171 +/- 15) were not significantly changed after leuprolide alone (153 +/- 18), and were decreased after adding dexamethasone (19 +/- 6; P less than 0.001). Andros-G levels did not increase significantly in normal women 60 min after i.v. ACTH (112 +/- 14 to 126 +/- 19), but rose in IH (170 +/- 24 to 216 +/- 26; P less than 0.001) and in PCO (179 +/- 26 to 238 +/- 31; P = 0.002). We conclude that Andros-G in women arises primarily from adrenal gland precursors and is elevated in hirsute women as a group. Its levels do not correlate with the severity of hirsutism, or the presence or absence of PCO, but reflect an increased production of adrenal androgens in both IH and PCO.     

COMPARATIVE EFFECTS OF SODIUM IPODATE AND IODIDE ON SERUM THYROID HORMONE CONCENTRATIONS IN PATIENTS WITH GRAVES'' DISEASE

Patients with thyrotoxic Graves' disease were treated daily for 10 d with 1 g sodium ipodate, an iodine rich X-ray contrast agent which impairs outer ring (5'-) deiodination of T4 to T3, or with 12 drops of a saturated solution of potassium iodide (SSKI). T4, T3 and reverse T3 (rT3) concentrations were measured before, during, and 5 and 10 d after the administration of each drug. SSKI therapy induced a decrease in the serum T4 concentration from 14.7 +/- 1.3 microgram/dl (mean +/- SE) to a nadir of 7.9 +/- 0.9 on days 9 and 10 of therapy, all values reaching the normal range by day 9; a decrease in the serum T3 concentration from 402 +/- 43 ng/dl to a nadir of 143 +/- 20 on day 10, remaining elevated in all patients until day 5 and decreasing into the normal range in all except one patient on days 9 and 10; and no change in the serum rT3 concentration. Serum T4 and T3 concentrations returned to baseline values 10 d after withdrawal of SSKI. In contrast sodium ipodate therapy induced only a modest decrease in the serum T4 concentration from 15.1 +/- 0.7 micrograms/dl to a nadir on day 9 of 11.3 +/- 1.0 and serum T4 remained above the normal range in most patients until day 8; a striking and rapid decrease (within 12 h) in ther serum T3 concentration from 340 +/- 36 ng/dl to mean values ranging from 79 to 85 during the last 5 d of therapy, with most values below the normal range during the last 3 d; and a marked increase in the serum rT3 concentration from 111 +/- 15 ng/dl to a peak value of 376 +/- 59 on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)     

SERUM STEROIDS IN NORMAL MALES AND PATIENTS WITH PROSTATIC DISEASES

The subjects investigated comprised 57 normal males between 30 and 80 years of age; 40 patients between 50 and 80 years of age suffering from benign prostatic hypertrophy (BPH), and 11 untreated prostatic carcinoma (Ca) patients aged between 57 and 79 years. Serum concentrations of oestradiol, pregnenolone, progesterone, 17alpha-hydroxyprogesterone, androstenedione, testosterone, 5alpha-dihydrotestosterone and androsterone were determined from a single serum sample (1.6 ml). Oestradiol was determined by an automated non-chromatographic radioimmunoassay, while other steroids were determined by radioimmunoassays, after solvent extraction and chromatographic purification on Lipidex-5000TM microcolumns. When patient groups were compared with the 25 normal males between 50 and 80 years of age, several conclusions could be drawn. Serum concentrations of 5alpha-dihydrotestosterone (P less than 0.01) and 17alpha-hydroxyprogesterone (P less than 0.001) were both significantly higher in the BPH patients when compared with the normal males. This trend was also apparent in the serum concentrations of progesterone and testosterone in the older BPH patients. Although the mean concentrations of 5alpha-dihydrotestosterone and 17alpha-hydroxyprogesterone were slightly higher in carcinoma patients than normal males, these differences were not statistically significant. No differences were seen in the concentrations of pregnenolone, androstenedione, androsterone and oestradiol between normal subjects and patients with BPH or prostatic Ca.     

SERUM THYROGLOBULIN IN PATIENTS WITH AUTONOMOUS THYROID NODULES

To investigate further the relationship between thyroid hormones and thyroglobulin (TG) secretion, total and free thyroid hormone levels, TSH and its response to TRH and serum TG concentrations were determined in 61 patients with solitary autonomous thyroid nodules. Thyroid function varied widely from euthyroidism to clearcut thyrotoxicosis. Serum TG levels were significantly higher in patients than in normal controls. Individually they were above the normal range (greater than 50 ng/ml) in 95% of the patients, as well as in those with normal total and/or free thyroid hormone levels. Patients with high total and/or free thyroid hormone levels had higher TG concentrations than euthyroid patients. TG concentrations were significantly correlated with FT3 values. They were higher in patients in whom TSH was unresponsive to TRH than in the responsive groups. TG was also slightly higher in patients with hot nodules than in those with warm nodules. These data seem to indicate that TG is secreted along with thyroid hormones in the absence of any stimulatory action. It also is a sensitive index of thyroid hyperfunction. Twenty patients were controlled 6 months after nodulectomy. TG levels, though significantly lower than in the preoperative state, were still higher than in normal subjects. This increase was attributed to persistent hyperthyroidism in two patients only. The observation that the increase in TSH after TRH stimulation in post-operative patients was greater than that found in normal controls led us to believe that in most cases the high TG levels after surgery are due to stimulation of the normal thyroid tissue by rebound TSH secretion.     

SERUM SEX HORMONE CONCENTRATIONS IN INSULIN DEPENDENT DIABETIC WOMEN WITH AND WITHOUT AMENORRHOEA

Abnormal steroid secretion may contribute to anovulation in insulin dependent diabetic patients with amenorrhoea. We have measured serum sex hormone-binding globulin (SHBG) and free and bound oestrogen and androgen levels in 17 such patients. As controls we included 17 patients with insulin dependent diabetes mellitus and normal menstrual cycles, 21 regularly menstruating normal women (both sampled during early follicular phase), and 23 non-diabetic patients with amenorrhoea. The diabetic patients with normal cycles had significantly higher serum concentrations of delta 4-androstenedione and testosterone than the normal women (P less than 0.01). The amenorrhoeic diabetics in contrast had significantly lower serum concentrations of SHBG, 5 alpha-dihydrotestosterone and free and total oestradiol-17 beta than either group of menstruating women (P less than 0.05), and significantly lower concentrations of delta 4-androstenedione (P less than 0.01), dehydroepiandrosterone sulphate (P less than 0.01), testosterone (P less than 0.01), and oestrone (P less than 0.05), than the cycling diabetics. The two amenorrhoeic groups had similar free and bound sex hormone concentrations except that delta 4-androstenedione levels were significantly lower in the diabetics (P less than 0.01). We conclude that the low sex hormone levels in diabetic women with amenorrhea may be due to suppression of the hypothalamic-pituitary axis in view of the impaired LH secretion found in these patients and that excess androgen secretion seems not to be of aetiological importance in amenorrhea related to diabetes mellitus. The decreased steroid levels in amenorrheic diabetics is due to their suppressed ovarian function while the increased androgen levels in diabetics with regular cycles are probably of ovarian origin.     

BONE MASS IN HIRSUTE WOMEN WITH ANDROGEN EXCESS

The spinal and femoral bone mass of 32 hirsute women with oligomenorrhoea and androgen excess was measured using dual photon absorptiometry and compared with the bone mass of 32 control women with regular menstrual cycles. Despite significantly lower oestradiol levels in the hirsute population there was no significant difference in the bone mass. Furthermore there was no significant difference in bone mass in five hirsute women with undetectable levels of oestradiol. It is concluded that androgen excess can maintain normal bone mass in the face of low or undetectable oestradiol levels.     

DOPAMINERGIC CONTROL OF GONADOTROPHIN SECRETION IN NORMAL WOMEN AND IN PATIENTS WITH PATHOLOGICAL HYPERPROLACTINAEMIA

The role of dopaminergic mechanisms in the control of gonadotrophin secretion in normal and hyperprolactinaemic subjects is controversial. Whilst bromocriptine, a potent dopamine agonist, has been used to restore normal gonadotrophin secretion in subjects with pathological hyperprolactinaemia (PHP), dopamine and dopamine agonists have been reported to suppress basal and stimulated gonadotrophin release. We therefore investigated the importance of dopaminergic control of gonadotrophin secretion by studying LH, FSH and PRL responses in normal and PHP subjects to central dopamine synthesis inhibition using monoiodotyrosine (MIT) and to a 4 h dopamine infusion designed to elevate peripheral plasma dopamine concentration to levels reported for pituitary portal plasma (1-6 ng/ml). MIT administration resulted in a significant release of PRL (peak increment 520 +/- 84% above basal) but not of LH or FSH in normal subjects. In PHP subjects there was a blunted PRL response (peak 13.3 +/- 3.5%) to MIT administration and significant LH (P less than 0.05) but not FSH release. Dopamine infusion (0.5 microgram/kg/min) resulted in suppression of PRL (min 19 +/- 3% of basal) but not of LH or FSH. A rebound of PRL (peak 188 +/- 68% of basal) but not LH or FSH occurred on cessation of dopamine. There was an apparent rise in LH (P less than 0.02 vs. normals) but not FSH in PHP patients during dopamine infusion. Plateau dopamine levels achieved during the infusion were 2.9 +/- 0.3 ng/ml and 5.9 +/- 0.8 ng/ml in normal and PHP subjects respectively. The responses to MIT show that dopamine functions as an inhibitor of PRL but not of LH or FSH in normal subjects. In PHP patients the responses suggest increased dopaminergic inhibition of LH release but loss of inhibitory control of PRL release. Physiological concentrations of plasma dopamine do not significantly inhibit LH or FSH release in normal subjects but paradoxically results in an apparent release of LH in PHP patients. We conclude that dopamine mechanisms do not play a significant role in modulating gonadotrophin release in normal subjects. In PHP patients, PRL feedback results in increased hypothalamic dopamine activity which in turn inhibits LH release. We conclude that the inhibitory action of dopamine on PRL release restores LH secretion by removing central dopaminergic inhibition through hypothalamic feedback of PRL.     

SERUM FSH, LH AND PROLACTIN IN NORMAL MALES AND PATIENTS WITH PROSTATIC DISEASES

Serum FSH, LH and prolactin were measured in fifty-eight normal males between 30 and 80 years of age. At the same time, similar estimations were performed on samples taken from 232 patients with benign prostatic hypertrophy (BPH) and twenty-six patients with prostatic carcinoma. The three groups were compared with respect to age, and it was observed that significant rises related to age occurred in the serum levels of FSH, LH and prolactin in normal men after the sixth decade. The patient groups did not differ significantly from each other, or from the normal age-matched population in respect to prolactin and FSH levels. Serum LH in both the carcinoma and BPH patient groups, however, differed significantly from the controls, and remained at the level associated with younger normal males. It is suggested that testosterone metabolites from the prostate exert a negative feedback on pituitary LH secretion.     

ADRENAL STEROIDOGENESIS IN HIRSUTE WOMEN

Adrenal steroidogenesis has been studied in vivo in ten hirsute and ten normal women. Serum levels of nine steroids on the biosynthetic pathway: the Δ⁵3 β-hydroxysteroids, pregnenolone (Pe), 17α-hydroxypregnenolone (17 Pe), dehydroepiandrosterone (DHEA), androstenediol (Adiol), and their Δ⁴3 keto counterparts, progesterone (Po), 17α-hydroxyprogesterone (17 Po), androstenedione (Adione), and testosterone (T), as well as cortisol, were measured following ACTH stimulation from a dexamethasone-suppressed state. The results are complicated by the finding of marked heterogeneity in the adrenal steroid response between different subjects in the normal population. One of the ten normal women had a much greater increment of Po and 17Po than the others following ACTH stimulation, suggesting that she has reduced 21-hydroxylase activity. A similar heterogeneity was also seen in the hirsute women, three of the ten having an exaggerated 17Po response to ACTH. Two of the same hirsute women also had greater Adione responses than normal. Adrenal steroidogenesis was normal in most of the hirsute women, while a subtle adrenal variant, possibly of 21-hydroxylase, has been demonstrated in a minority as in normal individuals; we do not yet know whether this is of aetiological importance. Our data do not support previous suggestions that adrenal 3β-hydroxysteroid dehydrogenase activity is reduced in hirsute women.     

FREE THYROID HORMONE LEVELS AND TSH RESPONSE TO TRH IN PATIENTS WITH AUTONOMOUS THYROID ADENOMATA AND NORMAL T3 AND T4

Free thyroid hormone levels together with basal and TRH stimulated TSH levels, have been determined in 50 patients with autonomous thyroid adenomata, who had normal serum total T3 and T4 values. Similar measurements were made in 33 healthy subjects. FT3 and FT4 plasma levels were significantly higher (P less than 0.01 and P less than 0.05 respectively), and basal and TRH stimulated TSH were significantly lower (P less than 0.05 and P less than 0.001 respectively) in the patients than in the controls. The TSH response to TRH was decreased in spite of normal free thyroid hormones in 25 patients and in a further ten both the delta TSH after TRH and the free fractions were normal. Eighteen patients were studied over periods from 4 37 months by repeating thyroid hormone levels and TRH tests. In six of them a change of these parameters toward toxicity was observed. The data obtained in the longitudinal study indicate that the values of free thyroid hormones and the result of the TRH test obtained by a single determination may represent different steps in the evolution of autonomous thyroid adenomata rather than a distinct pathophysiological condition.     

HIGH INCIDENCE OF NORMAL THYROID GLAND VOLUME IN PATIENTS WITH GRAVES'' DISEASE

Thyroid function and thyroid gland volume, ultrasonically determined, were investigated in ninety consecutive untreated patients with Graves' disease. Twenty-eight patients (31%) had no clinically detectable goitre. Median thyroid gland volume was 31 ml (range 12-99 ml). Twenty-one patients (23%) had a normal calculated thyroid volume. Thyroid volume did not correlate with any measure of thyroid function. The lack of a goitre in a large portion of patients with Graves' disease could be responsible for delayed diagnosis and subsequent treatment of these patients.     

SERUM LUTEINIZING HORMONE AND FOLLICLE STIMULATING HORMONE IN NORMAL CHILDREN AND PATIENTS WITH VARIOUS CLINICAL DISORDERS

Serum concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined in 329 normal children and 185 individuals with endocrinological abnormalities or variations of development. A significant increase of gonadotrophins is noted at the onset of puberty among the boys and at menarche for girls. The values are compared with serum concentrations of LH and FSH in children with abnormalities of sexual development, pituitary malfunction as well as other clinical abnormalities. Comparable levels for age and stage of development were found for premature thelarche, premature adrenarche, cryptorchidism, male pseudohermaphroditism and pubertal gynaecomastia. Hypogonadal individuals (Klinefelter's and Turner's syndrome, pure ovarian dysgenesis and testicular dysgenesis) have markedly elevated values while those with pituitary hypofunction had low values. Patients with sexual prococity tended to have elevated concentrations.     

SERUM FREE THYROXINE CONCENTRATION AND FREE THYROID HORMONE INDICES IN NORMAL PREGNANCY

Serum free thyroxine (FT4) concentrations were shown to be significantly reduced at 36-38 weeks normal pregnancy, both as measured FT4 by the Amerlex method (P less than 0.001), and as calculated FT4 (P less than 0.001) using accepted molecular weight and affinity constant data for the binding proteins. Serum FT4 concentrations as determined by the Immophase method were normal at 36-38 weeks normal pregnancy. All methods gave normal serum FT4 concentrations in subjects taking the oral contraceptive pill. FT4I and FT3I, derived using the MAA T3 uptake-value, were higher than normal at 36-38 weeks pregnancy (P less than 0.001), whereas T4/TBG and T3/TBG were both reduced (P less than 0.001). The observation that serum FT4 concentrations may fall in late pregnancy, as demonstrated both by the Amerlex radioimmunoassay technique and by calculation, suggests that circulating FT4 may not be the sole determinant of thyroid status at this time. From a practical viewpoint, it is important to note that currently available direct and indirect methods of assessing serum FT4 concentrations produce different patterns of change in pregnancy.     

LONG-ACTING THYROID STIMULATOR AND THYROID FUNCTION IN RELATIVES OF PATIENTS WITH GRAVES''DISEASE

In ten families, fifty relatives and seven husbands of ten patients with untreated Graves’disease were submitted to clinical examination, biological and immunological investigations. They were compared with fifty control subjects. In the relatives, thyroid diseases were found in 26%, positive LATS-IgG responses in 30%, thyroid antibodies in 23% and abnormal NBEI in 30%. The mean LATS response was significantly greater than in controls. With one exception no overt hyperthyroidism was found in the relatives on the basis of serum PBI, T₃ resin uptake test, total T₄ and TSH level. From the analysis of the pedigrees, no definite mode of inheritance can be found for LATS and NBEI. These data suggest the existence of a thyroid metabolic anomaly in the families of patients with thyrotoxicosis and argue against LATS as the cause of the hyperthyroidism of Graves’disease.     

ELEVATION OF SERUM ALUMINIUM CONCENTRATIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH DRUGS CONTAINING ALUMINIUM

In a group of 19 rheumatoid arthritis (RA) patients with normalrenal function, serum levels of aluminium (A1S) were monitoredduring treatment with drugs containing this metal (Al). The A1S levels during treatment were significantly higher (0.005>p>0.01)than those before treatment, i.e. 19.4 (SEM 2.3)µg/1 and12.3 (1.7), respectively. This increase in A1S was significantly(0.025>p>0.05) correlated with the pretreatment serumcreatinine level (mean value for the whole group 80.5 (SEM 4.7)mol/1) but showed no correlation with the predicted creatinineclearance. Although the increase in A1S during therapy withAl containing drugs is not dramatic in RA patients with normalrenal function, the rheumatologist should be aware of the riskof increased A1S concentration in RA patients, especially thosewith impaired renal function. KEY WORDS: Renal function, Trace metals, Arthritis, Elderly, Toxicity