Acidic isoforms of chorionic gonadotrophin in European and Samoan women are associated with hyperemesis gravidarum and may be thyrotrophic.

OBJECTIVE: There is conflicting evidence concerning the role of human chorionic gonadotrophin (hCG) in the aetiology of hyperemesis gravidarum (HG); particular isoforms of hCG may be the critical factor. Ethnic differences in HG prevalence and putative thyrotrophic effects of hCG may also relate to differences in hCG isoform profiles. To address these issues we examined the relationship of hCG isoforms to HG and thyroid function tests in two groups of women from ethnic backgrounds with significantly different HG prevalence rates. PATIENTS AND DESIGN: We enrolled 10 European and 10 Samoan women with HG and an equally sized non-hyperemetic, gestational stage matched control group. MEASUREMENTS: We administered a questionnaire, generated serum hCG charge-isoform profiles by chromatofocusing and measured the serum concentrations of total hCG, oestradiol (E2), thyrotrophin (TSH) and free thyroxine (FT4). RESULTS: The mean serum total hCG levels were highest in the Samoan hyperemetics (176,268 IU/l), and overall higher in hyperemetics compared with controls (159,770 IU/l vs. 86,420 IU/l, P < 0.001). When compared with controls, hyperemetics displayed increased hCG concentrations in the more acidic half (pH < 4) of the chromatofocusing pH range (89,843 IU/l vs. 41,146 IU/l, P < 0.003). Serum E2 levels did not differ between the four groups, but correlated with the hCG concentration between pH 5.2 and 4.01. Mean serum TSH levels were significantly lower in hyperemetics than in controls (0.33 mIU/l vs. 1.19 mIU/l, P < 0.001) and correlated with the hCG concentration between pH 4.6 and 2.8, while serum FT4 correlated with the hCG concentration below pH 4.0. CONCLUSIONS: Acidic isoforms of hCG may play a role in the aetiology of HG and gestational thyrotoxicosis. Minor ethnic differences in hCG isoform profiles were observed, but the relationship of acidic hCG isoforms to HG and serum thyroid hormone levels was largely independent of the patients' ethnicity. The mechanisms by which acidic isoforms might provoke nausea remain uncertain, but do not seem to involve E2, while the longer half-life of acidic hCG isoforms may result in increased in vivo TSH receptor cross-talk with resultant thyrotrophic effects.

Inhaled beclomethasone dipropionate suppresses the hypothalamo-pituitary-adrenal axis in a dose dependent manner.

OBJECTIVE: Little is known about the dose-response relationship of potential, unwanted, effects of inhaled beclomethasone (BDP) on the hypothalamo-pituitary-adrenal (HPA) axis, particularly in nonspecialist clinic settings. The purpose of our study was to investigate the dose-response relationship of inhaled BDP on the HPA axis in a general practice patient population. We also explored the optimal testing strategy in this population and correlated effects of inhaled BDP on the HPA axis with other systemic corticosteroid side effects. PATIENTS AND DESIGN: Controlled observational study employing 21 patients on inhaled BDP recruited from general practice, with minimal past and no present exposure to other corticosteroids, and 21 age and gender-matched controls. MEASUREMENTS: Twenty-four-hour urinary free cortisol excretion (UFC), serum cortisol before and 30 minutes after injection of 1 microgram and 250 micrograms of tetracosactrin, serum IGF-I and serum osteocalcin were measured. BDP use was estimated by inhaler weighing and prescription count. RESULTS: In subjects on inhaled BDP, 24-hour UFC (P < 0.008), serum cortisol 30 minutes after 250 micrograms tetracosactrin (P < 0.05) and the serum cortisol rise after 250 micrograms tetracosactrin (P < 0.04) were significantly lower when compared with controls. Measurements of HPA function correlated inversely with BDP dose estimated by inhaler weighing (all P < 0.03). Serum IGF-I and osteocalcin levels did not differ. CONCLUSIONS: We have demonstrated hypothalamo-pituitary-adrenal axis suppression in nonspecialist-clinic asthma patients on moderate to large doses of inhaled beclomethasone dipropionate. When accurate measurements of inhaled steroid dose are used, there is an exponential relationship between dose and hypothalamo-pituitary-adrenal axis suppression. There appears to be no 'safe' threshold, and around 15% of patients may have clinically significant suppression. However, the significance of hypothalamo-pituitary-adrenal axis suppression as a marker for concomitant corticosteroid effects on other organ systems remains uncertain.

Treatment of hypothyroidism with once weekly thyroxine.

We compared daily T4 therapy with 7 times the normal daily dose administered once weekly in 12 hypothyroid subjects in a randomized cross-over trial. At the end of each treatment we measured serum free T4 (FT4), free T3 (FT3), rT3, and TSH levels and multiple markers of thyroid hormone effects at the tissue level repeatedly for 24 h. Compared with daily administration, the mean serum TSH before the administration of weekly T4 was higher (weekly, 6.61; daily, 3.92 microIU/mL; P < 0.0001), and the mean FT4 (weekly, 0.98; daily, 1.35 ng/dL; P < 0.01) and FT3 (weekly, 208, daily, 242 pg/dL; P < 0.01) were lower. A minimally elevated serum total cholesterol during weekly administration (weekly, 246.8; daily, 232.6 mg/dL; P < 0.03) was the only evidence of hypothyroidism at the tissue level. Compared with daily administration, the mean peak FT4 following weekly administration of T4 was significantly higher (weekly, 2.71; daily, 1.59 ng/dL; P < 0.0001), as was the mean peak FT3 level (weekly, 285; daily, 246 pg/dL; P < 0.01). None of the tissue markers of thyroid hormone effect changed compared to daily T4, and there was no evidence of treatment toxicity, including cardiac toxicity. During weekly T4 administration, autoregulatory mechanisms maintain near-euthyroidism. For complete biochemical euthyroidism a slightly larger dose than 7 times the normal daily dose may be required.

Effect of cortisol on percentage of non-sex-hormone-bound steroid: implications for distribution of steroids on binding proteins in serum.

We previously observed that in men concentrations of serum testosterone (T) not bound to sex-hormone-binding globulin (n-SHBGT) decreased as concentrations of cortisol increased in early morning. This led us to investigate in vitro the influence of several steroids on protein-bound T. Steroids were added to late-evening sera containing low concentrations of cortisol. Changes were measured in percent T or estradiol not bound to SHBG (%n-SHBGT or %n-SHBGE). Results were compared with computer simulations of a mass action model describing current understanding of steroid binding to serum proteins. In vitro measurements confirmed changes observed in vivo. Cortisol at 600 nmol/L reduced %n-SHBGT to 61% +/- 5% of basal, but this was reversed with cortisol at 2000 nmol/L. Progesterone reduced %n-SHGBT less, and dexamethasone had no effect. Free T rose with added cortisol. Increasing estradiol to 900 nmol/L caused an increase in %n-SHBGT. The %n-SHBGE rose with added cortisol (121% +/- 5% of basal with cortisol at 1000 nmol/L). Simulation predicted all behaviors except the marked initial decrease in %n-SHBGT as cortisol concentrations increased and the absolute values of %n-SHBGT and %n-SHBGE. A possible explanation for the former is that T is displaced from corticosteroid-binding globulin (CBG) by added cortisol, more T is bound to CBG than expected, and T displaced from CBG associates with SHBG rather than albumin. Alternatively, current understanding about steroid binding to serum proteins has other major deficiencies.

Serum free thyroxine levels in cats maintained on diets relatively high or low in iodine.

Excessive or deficient intake of iodine may play a role in the development of goitre and hyperthyroidism in cats. Previous investigations have shown that the serum free thyroxine level of cats is affected by brief administration of food high or low in iodine content. We have now measured serum free thyroxine levels in groups of cats fed relatively high or low iodine diets for much longer periods (5 months). In contrast to our earlier findings, the chronic ingestion of relatively high or low iodine diets did not lead to statistically significant differences in serum free thyroxine levels. The results of the present investigations show that the cat is able to maintain normal levels of thyroid hormone despite prolonged high or low iodine diets. It may be that the adaptive mechanisms that are called into play during chronic high or low iodine intake lead to thyroid disease, particularly in certain predisposed individuals.

Circadian variation in serum free and non-SHBG-bound testosterone in normal men: measurements, and simulation using a mass action model.

OBJECTIVE: We measured the changes in testosterone fractions in serum of normal men over a 24-hour period, and determined whether they could be simulated on the basis of current understanding of the interactions between steroids and binding proteins in the blood. DESIGN: Starting from between 0830 and 0930 h, blood samples were taken every 45 minutes for 25.5 hours. PATIENTS: Five healthy males aged 26-45 years. All participants worked on a hospital campus and while being sampled carried out their normal activities during waking hours. MEASUREMENTS: The concentrations of testosterone (RIA) and albumin, and the percentage non-sex hormone binding globulin-bound testosterone (ammonium sulphate precipitation) and percentage free testosterone (rate dialysis), were measured on each sample. Cortisol (RIA) and sex hormone-binding globulin (SHBG) (IRMA) concentrations were measured on every second sample, and that of corticosteroid-binding globulin on two samples from each series. RESULTS: In all participants the levels of free and non-SHBG-bound testosterone in early morning samples (near 0530 h) were significantly different from those taken before midnight (P < 0.0005). Significant circadian rhythms (P < 0.05) in the concentration of testosterone and in the level of the free fraction were detected in all participants, and in four of the five participants for the non-SHBG-bound fraction. The amplitude of the free testosterone rhythm (34 +/- 2% of basal) was greater than that for testosterone itself (24 +/- 3% of basal). The 24-hour rhythm of the non-SHBG-bound fraction was similar to the total and free fractions except for the period 0330-0900 h when the level of this fraction declined by 15-45% over 1.5-3 hours. This decline was coincident with the initial rise in the concentration of cortisol. A decline of 10.5 +/- SEM 1.0% in the concentration of albumin, and 12.0 +/- 1.1% in that of SHBG occurred when the mean ambulant and supine levels were compared; analysis indicated significant circadian rhythms in the concentrations of these proteins. Simulation was used to investigate possible causes for the circadian rhythms in free and non-SHBG-bound testosterone. Simulation results matched the measured data well in qualitative terms, but quantitatively there were differences. CONCLUSIONS: Increasing saturation of the binding proteins following rises in testosterone production, and the small but significant changes in protein concentration, probably related to postural changes, were implicated as the major factors in the rhythm amplitude. However, the early morning decline in the non-SHBG-bound fraction was not explained by these factors. The rise in cortisol concentration at this time is a probable cause. Alternatively, simulation suggests that a substance appearing in the early morning and competing with testosterone for albumin binding sites may be responsible.

The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand.

Two surveys of 12 months duration were undertaken on opioid users presenting to the Wellington Alcohol and Drug Centre before and after the introduction of a combination buprenorphine 0.2 mg-naloxone 0.17 mg tablet (Bu-Nx), which was launched in 1991 in the hope of reducing intravenous misuse. There was considerable intravenous (i.v.) misuse of buprenorphine 0.2 mg tablets (Bu) in 1990 with self-reports of misuse in 81% of the patients over the 4 weeks prior to presentation, and 65% of the patients had buprenorphine in their urine. In the repeat survey 57% reported misuse of the Bu-Nx combination over the previous 4 weeks, and 43% had buprenorphine +/- naloxone detected in their urine. There was a reduction in the street price of Bu-Nx. One-third of the patients who used Bu-Nx i.v. reported instances of withdrawal symptoms, and subjectively the drug was less attractive to misusers. The combination product may have less misuse potential than buprenorphine alone, but it remains a preparation, in the dosages employed, that is intravenously misused.

The efficacy of serum prostate specific antigen as a tumour marker in prostatic carcinoma: a comparison with serum acid phosphatase.

AIMS: To assess the efficacy of serum prostate specific antigen (PSA) in the diagnosis of prostatic cancer. To compare this tumour marker with serum acid phosphatase (ACP) in order to define the more effective diagnostic test. METHODS: Serum samples from 349 patients attending a urology department were assayed for PSA and ACP. Histological assessment of prostatic biopsy samples was used as the standard by which the diagnostic effectiveness of the tumour markers was determined. RESULTS: Mean serum PSA results from patients with prostatic carcinoma (159 (SEM 35) ng/mL) were significantly different to those from patients with benign prostatic hyperplasia (4.0 (0.53) ng/mL). As there was considerable overlap of results, test sensitivities and specificities were calculated for various decision points. The sensitivity and specificity of PSA at a level of 10 ng/mL were 61.2% and 93.0% respectively, while for ACP at a level of 0.8 U/L they were 47.6% and 89.9%. The areas beneath receiver-operator curves (0.81 for PSA and 0.72 for ACP) indicated that PSA gives better diagnostic information than ACP. For a stated incidence of cancer, posttest probabilities following a given PSA result have been calculated. CONCLUSIONS: PSA is a more effective serum marker for prostatic carcinoma than ACP. We present a table so that for similar patient groups posttest probabilities for prostatic cancer can be assessed for a given serum PSA level.

Platelet 3H-imipramine binding during recovery from depression.

Decreased binding of tritiated imipramine to platelets has been considered to be a potential biological marker of depression. However, it has been unclear how binding values alter during treatment and recovery. This study investigated imipramine binding parameters and depressive symptoms in 25 patients suffering from major depression at entry to the study and 1, 3 and 6 months later. Although the initial Bmax values were significantly lower in the depressed patients than in healthy subjects, it was not possible to establish a clear relationship between recovery from depression and Bmax. The power of this study to detect an effect of at least 10% of the variance in Bmax due to factors related to recovery from depression was 0.78.

Serum free thyroxine levels respond inversely to changes in levels of dietary iodine in the domestic cat.

Because of a perceived increase in the incidence of toxic multinodular goitres in cats in recent years, we investigated the iodine content of three varieties of commercial canned cat foods and studied the acute effects of 'ingestion of these preparations on urinary iodine excretion and serum free thyroxine levels in young, healthy cats. Ten castrated male cats were fed from a common source. The type of food was changed every 2 weeks. Urine and blood specimens were obtained weekly. Serum free thyroxine levels were determined and iodine concentrations in urine were assayed. The iodine content of the cats' food was also assayed. Food varieties of high, intermediate and low iodine content were fed for 2-week periods. There was a consistent, reciprocal relationship between the mean urinary iodine concentration and the mean serum free thyroxine level for each 2-week period. The difference in the mean serum free thyroxine concentrations for the high and low iodine intake periods was highly significant (p<0.01). When the serum free thyroxine level and the urinary iodine level for each cat at each collection throughout the 12-week study were analysed (66 paired results), a strong inverse correlation (r=0.59, p<0.01) was found. We concluded that the serum free thyroxine level in cats, as measured by a kit designed for human serum, is acutely responsive to changes in iodine intake.

Serum levels of free and bound testosterone in hyperthyroidism.

OBJECTIVE: The aim of this study was to improve knowledge about the relationships between free and bound forms of testosterone in serum and the major testosterone-binding proteins during hyperthyroidism. DESIGN: Nine men and 11 women were studied when hyperthyroid due to Graves' disease and again after at least 3 months of euthyroidism. MEASUREMENTS: The serum concentrations of free T3, free T4, TSH, sex hormone-binding globulin (SHBG), LH, progesterone and free, non-SHBG bound and total testosterone were determined. RESULTS: For both sexes, hyperthyroidism was associated with significant elevations of the mean total testosterone and sex hormone-binding globulin (SHBG) levels and significant depressions of the mean percentage and concentration of non-SHBG-bound testosterone and the mean percentage of free testosterone. For women, the mean free testosterone concentration was significantly lower during hyperthyroidism than during euthyroidism; no significant difference in mean free testosterone concentration was observed between hyperthyroid and euthyroid men. When the experimentally derived data were analysed according to a model based on the binding constants of testosterone with SHBG and albumin, the simulated results for each patient when hyperthyroid and euthyroid paralleled the actual results. However, the model consistently overestimated the actual amounts of non-SHBG-bound testosterone. There was a significant correlation between SHBG concentration and the severity of thyrotoxicosis as measured by the change in thyroid hormone levels between euthyroidism and hyperthyroidism. CONCLUSIONS: Our results support the following pathogenetic sequence: thyrotoxicosis leads to a rise in serum SHBG concentration which is accompanied by an increase in testosterone concentration, a fall in the concentration of non-SHBG-bound testosterone and little or no change in the concentration of free testosterone.

Platelet tritiated imipramine binding in patients suffering from mania.

Platelet imipramine binding was measured in 16 patients suffering from DSM-IIIR mania and compared with binding values reported in depressed and healthy control subjects recruited in a parallel study (Ellis et al., 1990). Binding levels in the manic group did not differ from control values, but were higher than in the depressed group. Within the manic group, binding did not differ with severity of illness or the presence of depressive symptoms but there was a trend to lower values (comparable to those in the depressed group) with increasing duration of illness. This raises the possibility that changes in imipramine binding in depression and mania may be similar, consistent with the permissive hypothesis of serotonin function.

Circadian variation in platelet imipramine binding during the day in healthy subjects.

Platelet tritiated imipramine binding values in healthy controls vary considerably from study to study. A possible contributor to such variation might be a circadian rhythm affecting binding, although previous studies of this have been contradictory. Platelet imipramine binding was examined in 12 healthy, medication-free subjects studied at 8 a. m., 11 a. m., 4 p. m., and 10 p. m. during one day. Imipramine binding was determined on platelet membranes, using 0.8-8 nM 3H-imipramine, and nonspecific binding was defined by 50 microM desipramine. All samples from a given individual were assayed simultaneously. The intra-assay coefficient of variation was 6.3 percent. There was no evidence of significant differences in binding capacity or affinity (Bmax or Kd) at different times of day. Circadian variation was explored using COSINOR analysis (DeMet et al., 1989). There was no evidence of circadian variation in binding using this model, even when only the variable portion of binding was considered for each individual. Intraindividual variation in binding was substantial, with a mean coefficient of variation of 29 percent for Bmax and 38 percent for Kd. The possible basis of this variation is unclear, but may reflect the presence of "occult" binding sites in the membrane, or the effect of endogenous modulators of binding. The interrelationship of Bmax and Kd may also be a factor. It was considered that low-affinity binding did not account for a significant part of the variation in Kd in this assay. The utility of imipramine binding as a biological marker of depression may be limited by such levels of intraindividual variation in binding parameters.

Platelet tritiated imipramine binding in psychiatric patients: relationship to symptoms and severity of depression.

The clinical and research significance of reduced imipramine binding has remained unclear despite considerable investigation. This study used an assay of demonstrated reliability to investigate the clinical correlates of imipramine binding to platelets in 63 depressed and 33 nondepressed psychiatric patients and 40 healthy control subjects. Both patient groups had Bmax values significantly lower than those of the healthy controls. Unequivocal associations between binding parameters and individual symptoms or groups of symptoms were not established, but a negative correlation between Kd and the number of adverse life events experienced in the preceding 6 months was apparent. These findings provide no support for the view that reduced binding is a trait marker for susceptibility to depression and cast doubt on its specificity as a state marker for the syndrome of depression.

Serum forms of testosterone in men after an hCG stimulation: relative increase in non-protein bound forms.

A postulated function of steroid binding proteins in serum is to smooth changes in steroid levels. To test this, testosterone levels in six normal men were increased by injecting 6000 IU hCG i.m., and changes in serum forms of testosterone were measured. Blood was collected every 10 min for 2.5 h and then once a day for 4 days. By day 4 the mean serum testosterone level had risen to 178% +/- 13% (SEM) of a mean basal level (first five samples). This rise was less than that in free testosterone (221% +/- 18%), which was in turn less than the rise in the non-SHBG-bound fraction (255% +/- 19%). The concentrations of SHBG and albumin were constant. Thus, two putative bioactive fractions of testosterone, the free and non-SHBG-bound, increased to a greater extent than did total testosterone. Because the binding protein concentrations were constant, this implies they may act not as a buffer, but as an enhancer of active testosterone over this time interval.

Resolution of acromegaly after removal of a bronchial carcinoid shown to secrete growth hormone releasing factor.

A 29 year old woman with an enlarged pituitary fossa and classical acromegaly, possibly present for ten years, had biochemical and partial somatic resolution of the disorder after removal of a bronchial carcinoid tumour. In addition, galactorrhea stopped, menstruation returned after two years, and amenorrhea and elevated prolactin levels fell towards normal. Immunocytochemistry showed numerous growth hormone releasing factor (GRF) staining cells in the tumour. The tumour cells, when cultured, produced a supernatant selectivity stimulating human pituitary somatotrophic cell cultures to produce growth hormone (GH). The bronchial carcinoid did not secrete detectable GH, but extracts of it, and preoperative serum contained GRF immunoreactivity which coeluted with synthetic human pancreatic GRF.

The analysis of data from breast cancer estrogen and progesterone receptor assays: Scatchard plots are inferior to direct fitting by computer.

The advantages are illustrated of analyzing breast cancer estrogen and progesterone receptor assays by fitting a receptor-ligand binding model directly to experimental data, rather than using the common graphical transformation known as the 'Scatchard plot'. Analysis of laboratory experiments and the use of simulation show that while both methods give equivalent results, the direct approach has definite advantages. In particular, results are more reliable in the face of increasing experimental error, it is possible to quantify non-specific binding from the primary data rather than having to measure it separately, and the methodology readily lends itself to optimizing the design of experiments.

Thyroid function tests in acutely ill patients. Comparison of analogue based free thyroid hormone assays with free thyroxine index.

A prospective study of 100 acutely ill patients was carried out to assess the value of the free thyroxine (FT4) assay as a replacement screening procedure for the free thyroxine index (FTI). We found that the FT4 assay was significantly influenced by the albumin concentration, so that the number of follow-up tests required increased markedly. This was especially true at the low end of the FT4 range where the need for thyrotropin assays increased by 162%. The free triiodothyronine (FT3) assay was also shown to be albumin dependent. It is not useful to replace one set of difficulties due to protein binding with another, and overall it was concluded that it is not cost-effective to screen hospital patients for thyroid dysfunction using free hormone assays based on labelled analogue techniques.

The diagnostic distribution of dexamethasone non-suppressors.

Baseline serum cortisols and DSTs were performed on 100 psychiatric inpatients. The rates of non-suppression in selected DSM III diagnostic categories were calculated and the results discussed in the context of recent literature. It was concluded that test specificity may have been frequently overestimated. The suggestion is made that DST non-suppression may have non-specific and relative vector qualities, and thus be of little diagnostic use.