Plasma variation of corticosteroid-binding globulin and sex hormone-binding globulin.

Sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) circulate in plasma and bind their cognate ligands with high affinity, offering a steroid delivery system to target tissues by a variety of mechanisms. Analysis of these steroid-binding proteins is gaining importance in the clinical setting, although more information is warranted on their diurnal and biological variation. This study shows that plasma SHBG (in normal subjects) exhibits little diurnal or biological variation over the 30 day period studied, in contrast to CBG, where plasma levels peak in the early afternoon. This leads to attenuation of the diurnal free cortisol level rhythm compared to total cortisol. We also show that plasma CBG is significantly lower in male subjects with the metabolic syndrome compared to age-matched lean counterparts, and may therefore act as a surrogate marker of insulin resistance. The consequence of lower levels of CBG in these obese male subjects is reflected by higher levels of circulating free cortisol, potentially offering a more favourable environment for adipogenesis.

Paget's disease complicated by hydrocephalus and syringomyelia.

The authors report a case of Paget's disease involving the skull with the rare but severe complications of hydrocephalus and syringomyelia related to basilar impression. Complications of Paget's disease of the skull are briefly discussed and current treatment strategies outlined.

Contribution of growth hormone-releasing hormone and somatostatin to decreased growth hormone secretion in elderly men.

OBJECTIVE: The pathophysiology of the decline in circulating growth hormone (GH) concentrations that may occur with ageing remains elusive. We have investigated the potential contributions of decreased endogenous GH-releasing hormone (GHRH) and increased somatostatin secretion to this phenomenon. DESIGN AND METHODS: The strategy used was to stimulate GH secretion in 8 young (20-24 years old, body mass index (BMI) 22.8 +/- 2.8 kg/m2) and 8 elderly (68-82 years old, BMI 23.4 +/- 1.6 kg/m2) male subjects on separate occasions by means of: (i) intravenous bolus 0.5 microgram/kg D-Ala2 GHRH(1-29)-NH2 alone; (ii) 0.5 microgram/kg GHRH after pre-treatment with two oral doses of 50 mg atenolol (to inhibit somatostatin secretion); (iii) 1.25 mg oral bromocriptine alone (to increase endogenous GHRH and/or inhibit somatostatin); (iv) 50 mg oral atenolol plus 1.25 mg oral bromocriptine; and (v) 0.5 microgram/kg GHRH after pre-treatment with 1.25 mg oral bromocriptine. RESULTS: The elderly men had a significantly lower peak and area under curve (AUC) GH response to intravenous GHRH when compared with 8 young men (peak 3.1 +/- 1.0 ng/ml v. 21.6 +/- 5.0 ng/ml, AUC 205 +/- 56 ng/ml/min v. 1,315 +/- 295 ng/ml/min, P < 0.05). Pre-treatment with atenolol before GHRH administration produced no significant increase in peak and AUC GH response in both groups, which remained lower in the elderly men than in their young counterparts (peak 5.5 +/- 1.8 ng/ml v. 29.3 +/- 7.0 ng/ml, AUC 327 +/- 90 ng/ml/min v. 2,017 +/- 590 ng/ml/min, P < 0.05). Bromocriptine alone did not cause a significant rise in GH concentration in either elderly or young subjects (peak 3.1 +/- 1.1 v. 8.8 +/- 3.2 ng/ml, P > 0.05). When atenolol was administered before bromocriptine, both groups responded but the elderly subjects had a significantly greater peak and AUC response (peak 3.6 +/- 0.7 v. 10.7 +/- 2.1 ng/ml; AUC 191 +/- 39 v. 533 +/- 125 ng/ml/min, P < 0.05). Bromocriptine given before GHRH failed to potentiate GHRH action on GH release in either group. Of 5 elderly men who underwent further evaluation of GH secretory ability, 2 subjects had GH levels > 10 ng/ml, either basally or after intravenous GHRH. The remaining 3 had an initially impaired GH response to bolus intravenous GHRH. After 100 micrograms GHRH subcutaneously twice daily for up to 2 weeks the GH responses to intravenous bolus GHRH (0.5 microgram/kg) were reassessed. One exhibited a normal response (> 10 ng/ml) after 1 week of daily GHRH treatment, another had a near-normal response after 2 weeks (9.7 ng/ml), while the third still had an impaired response by the end of the 2-week treatment period (3.2 ng/ml). CONCLUSIONS: The restoration of endogenous GH secretion in these elderly subjects by means of GHRH priming, and the failure of manipulation of somatostatinergic tone to restore a normal GH response to GHRH suggests that somatotroph atrophy due to a reduction in endogenous GHRH secretion is the principal cause of the diminished GH secretion with ageing.

Acromegaly in the developing world--a 20-year teaching hospital experience.

A retrospective analysis was conducted to examine the long-term outcome of surgery, by a single pituitary surgeon and radiotherapy for acromegaly at Groote Schuur Hospital, Cape Town, using modern criteria for the definition of cure. Seventy-two patients (F/M ratio 1.3:1), aged 16-74 years, were eligible for inclusion. The mean follow-up period was 8.3 years. Macroadenomas were present in 79%, microadenomas in 15% and tumour size was not documented in 6%. Pretreatment GH levels were, > or = 40 m U/l in 56 patients. Postoperatively, 21% of patients were cured, 40% controlled and 40% had hypopituitarism. After radiotherapy (mean follow-up 8.7 years) 43% were cured, 66% controlled and 78% had hypopituitarism. At follow-up 37% of patients traced had died. The most common cause of death was vascular disease. The poor surgical results may be attributed to late presentation in the developing world setting, as evidenced by tumour size and invasiveness, and the degree of GH elevation. Emphasis on early diagnosis of non-invasive tumours is necessary to improve the cure rate and reduce mortality,

Primary hypoadrenalism assessed by the 1 microg ACTH test in hospitalized patients with active pulmonary tuberculosis.

Primary hypoadrenalism, assessed by 250 microg ACTH stimulation, is uncommon in patients with active pulmonary tuberculosis (PTB). Since 1 microg ACTH produces an equivalent +30 min cortisol response to 250 microg in control subjects, the 250 microg dose is supraphysiological and may lack sensitivity for the diagnosis of hypoadrenalism. Furthermore, the impact of coexistent HIV infection on the prevalence of primary hypoadrenalism in PTB is uncertain. We thus determined the cortisol response to an intravenous bolus of 1 microg ACTH in 21 controls, 18 HIV-positive (BMI 19.5+/-0.9 kg/m(2), albumin 24+/-1.4 g/l, CD4 count 192+/-47/mm(3)) and 22 HIV-negative (BMI 19.3+/-0.8 kg/m(2), albumin 29+/-1 g/l, CD4 count 652+/-76/mm(3)) patients with active PTB. The mean basal cortisol was greater in patients than in controls (559 vs. 373 nmol/l, p=0. 0009). The mean cortisol after 1 microg ACTH stimulation did not, however, differ significantly when comparing either patients and controls or patients who were HIV-positive and -negative (p>0.05). Using the minimum +30 min cortisol derived from the 21 controls as a marker of normal adrenal function (414 nmol/l), a single patient was classified as hypoadrenal. In conclusion, primary hypoadrenalism, as assessed by the 1 microg ACTH test, is uncommon in a cohort of ill, hospitalized patients with active PTB, irrespective of HIV status.

Effects of anabolic-androgenic steroid use or gonadal testosterone suppression on serum leptin concentration in men.

OBJECTIVE: Serum leptin concentration shows a sexual dimorphism that is not accounted for by gender differences in adiposity. A strong inverse association exists between serum leptin and testosterone concentrations in men, pointing to a likely influence of gonadal sex steroids on serum leptin concentration. The aim of this study was to investigate whether manipulation of sex steroid hormones in men would alter serum leptin concentration independently of changes in fat mass. DESIGN AND METHODS: The effects of sex steroid suppression on serum leptin concentration were investigated in nine healthy men in whom testosterone had been reversibly suppressed for 5 weeks after treatment with intramuscular triptorelin. The effects of sex steroid supplementation were investigated in nine male bodybuilders who self-administered anabolic--androgenic steroids (AAS) for a mean period of 6.5 weeks. A control group received no hormonal treatment. RESULTS: Testosterone concentration was significantly reduced by triptorelin administration (7.32+/- 1.92ng/ml at baseline compared with 1.15+/-0.57ng/ml at 5 weeks, P=0.002). High-dose AAS use was confirmed by urine analysis. Body fat percentage was unaffected by the AAS or triptorelin intervention (P>0.19). Leptin concentration was significantly reduced after one cycle of AAS use (2.40+/-0. 98ng/ml off cycle compared with 1.63+/-0.37ng/ml on cycle, P=0.012), and was significantly increased by triptorelin administration (2. 96+/-1.50ng/ml at baseline compared with 6.63+/-4.67ng/ml at five weeks, P=0.004). No significant change occurred in the control group. CONCLUSION: Androgenic sex hormone supplementation decreases serum leptin concentration, whereas suppression increases serum leptin concentration, independently of changes in body fat mass in healthy men. The sexual dimorphism evident in serum leptin concentration is likely to be due to a suppressive effect of testosterone on serum leptin concentration in males.

Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.

BACKGROUND: The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. METHODS: This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. RESULTS: Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. CONCLUSIONS: Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.

Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol.

For a period of 12 months all samples submitted for serum prolactin (PRL) assay and with PRL > 700 mU/L were examined by gel filtration chromatography. In 17 (25%) of 69 samples we found macroprolactin. The Delfia and Immuno 1 immunoassay systems gave similar PRL results with samples containing macroprolactin whereas the ACS 180 system gave lower results. With the Delfia and Immuno 1 systems samples containing substantial quantities of macroprolactin showed low recovery of PRL after precipitation with polyethylene glycol 6000 (PEG 6000) and this technique can be used as a screening test for macroprolactinaemia. We conclude that macroprolactinaemia is a common phenomenon and, in assays which detect this species, is a common cause of hyperprolactinaemia. Macroprolactinaemia may contribute to the difficulty in establishing an upper limit of the reference range for serum PRL. In our experience, patients with macroprolactinaemia do not exhibit features of the hyperprolactinaemia syndrome and it is important to recognize macroprolactin as the cause of hyperprolactinaemia to avoid unnecessary investigation and treatment.

The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy.

OBJECTIVE: Dopamine agonists are the primary therapeutic modality for the majority of patients with prolactinomas, with pituitary surgery reserved for those patients intolerant of or resistant to these agents. Most published surgical series, however, contain patients treated by surgery as the primary therapeutic modality. Previous exposure to dopamine agonists or the selection of patients with prolactinomas resistant to conventional therapy may potentially compromise the surgical success rate. The purpose of this study was to evaluate the efficacy and safety of pituitary surgery for prolactinomas in a tertiary referral centre where the majority of patients were operated on after treatment with dopamine agonists. DESIGN: A retrospective review of the outcome of pituitary surgery for prolactinomas performed at a tertiary neurosurgical centre by a single neurosurgeon. PATIENTS: Twenty-three patients underwent excision of a macro and 11 excision of a micro-prolactinoma. MEASUREMENTS: Pituitary tumour diameter was determined by CT or MRI imaging. Pre and post-operative measurements were made of serum PRL concentration (off dopamine agonist therapy), free T4, free T3, LH and testosterone (males). Post-operative restoration of a menstrual cycle was taken to indicate resolution of hypogonadism in female patients. RESULTS: The majority (73.9%) of the patients with macro and all with micro-prolactinomas had received dopamine agonists preoperatively. Of the 23 patients with macroprolactinomas, in whom the median preoperative PRL concentration was 13255 mU/l, 17 (73.9%) had radiological evidence of suprasellar extension and 5 (21.7%) cavernous sinus invasion. Only 4 (17.4%) of the patients with macroprolactinomas had a normal serum PRL post-operatively, although there was an improvement in visual fields in 66% of those with preoperative defects. The median preoperative PRL concentration was 4309 mU/l in the patients with microprolactinomas, significantly lower than in the macroprolactinoma group (P = 0.02). Despite a significant fall in serum PRL postoperatively (median PRL 860 mU/l, P = 0.0001), only 45.5% of patients had a normal serum PRL concentration after surgery. CONCLUSIONS: The cure rate following pituitary surgery for prolactinomas in a tertiary referral centre was low when compared with previous series in which surgery was used as the primary therapeutic modality. We suggest this may result both from dopamine agonist pretreatment and the referral of prolactinomas resistant to conventional therapy. The outcome is probably a more realistic reflection of the results of pituitary surgery for prolactinomas as currently practised in the majority of neuroendocrine centres.

The evaluation and management of subclinical pituitary disease.

The advent of sophisticated and sensitive radiologic techniques has undoubtedly improved the evaluation of patients with established endocrine disease. An inevitable consequence of the increased sensitivity and widespread availability of modern imaging is, however, the discovery of apparently asymptomatic mass lesions in endocrine tissues. The clinician is then required to determine the appropriate degree of often uncomfortable and costly investigation in a patient with no overt disease. This article attempts to provide guidelines for the management of the 'pituitary incidentaloma', a pituitary mass lesion evident on a computed tomography or magnetic resonance imaging scan performed for a reason other than the evaluation of the pituitary gland.

Neuroendocrinology of the polycystic ovary syndrome.

The clinical and biochemical heterogeneity of the PCOS is mirrored by the range of neuroendocrine disturbances described in women with PCOS. An increased serum LH concentration is a common, although not ubiquitous, feature and occurs primarily as a result of an increase in the amplitude of pulsatile LH, and presumably GnRH, secretion. The frequency of pulsatile GnRH secretion may, however, be increased in certain patients and may conceivably increase LH bioactivity by altering glycosylation of the molecule. Vigorous debate continues as to whether the observed changes in gonadotrophins are a primary abnormality or occur secondary to alterations in peripheral steroid concentrations. The proponents of the frequency hypothesis point to the discordant changes in gonadotrophin secretion that may be induced by rapid frequency exogenous GnRH stimulation in patients with hypogonadotrophic hypogonadism. Those who believe that the inappropriate gonadotrophin secretion is a secondary phenomenon argue that manipulation of peripheral steroid levels, by either administration of oestrogen/progesterone, induced ovulation or ovarian diathermy, may correct the disturbance of gonadotrophin secretion, which is therefore presumably a consequence of changes in ovarian steroid feedback signals. The weight of evidence at present suggests that the inappropriate gonadotrophin secretion is usually a secondary abnormality, although there may be groups of patients with a primary increase in GnRH pulsatility. The search for a unifying neuroendocrine disturbance in PCOS has been frustrated by the inability to find consistent evidence of disordered central dopaminergic, opioidergic, noradrenergic or serotoninergic pathways. Those abnormalities which have been uncovered appear to be secondary to chronic anovulation rather than of primary pathological import, and emphasize the central importance of the ovary as culprit rather than victim in PCOS.

Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism.

Recent guidelines propose that secondary hypoadrenalism can be reliably diagnosed, in the absence of acute ACTH deficiency or glucocorticoid use, by means of the short ACTH test (Synacthen). We report a patient who maintained a normal response to exogenous ACTH stimulation despite symptomatic chronic ACTH deficiency proven by the insulin tolerance and overnight metyrapone tests. It is suggested that partial ACTH deficiency may prevent involution of the adrenal cortex and preserve the cortisol response to ACTH stimulation. A normal cortisol response in the short ACTH test does not therefore exclude the possibility of clinically relevant ACTH deficiency.

Osteopenia as a feature of the androgen insensitivity syndrome.

OBJECTIVE: The syndrome of androgen insensitivity, a paradigm of a hormone resistance syndrome, manifests as failure of masculinization despite normal or high concentrations of serum testosterone. The defect in these 46 XY patients resides in the androgen receptor gene, with consequent defective androgen action and abnormal sexual differentiation. We sought to evaluate whether the adverse sequelae of androgen resistance may extend to skeletal tissue by measuring bone mineral density in six patients with androgen insensitivity. DESIGN: A cross-sectional retrospective study. MEASUREMENTS: Bone mineral density was measured by means of a Dexa (Hologic QDR 1000 scanner). The diagnosis of androgen insensitivity was confirmed in each patient by karyotype and assay of sex hormones. RESULTS: The five adult patients with androgen insensitivity had been exposed to both defective androgen action and variable periods of oestrogen deficiency. The latter resulted from the low circulating oestrogen concentrations (for premenopausal females) before gonadectomy and inadequate oestrogen replacement after gonadectomy. All five adults with androgen insensitivity had osteopenia in both the lumbar spine (T-score -1.52 to -3.85) and femoral neck (T-score -1.34 to -4.91). CONCLUSIONS: Osteopenia in patients with androgen insensitivity may relate to defective androgen action, oestrogen deficiency or a combination of the two. These observations have implications for the management of patients with androgen insensitivity and may provide insight into the effects of androgens on the female as well as the male skeleton.

Transient diabetes insipidus in pregnancy--a consequence of enhanced placental clearance of arginine vasopressin.

We report a patient who presented with transient diabetes insipidus in pregnancy on a background of previous postoperative diabetes insipidus following surgical excision of a prolactinoma. The patient illustrates how the complex changes in water homeostasis occurring during normal pregnancy may unmask latent diabetes insipidus. The major factors operating appear to be a physiological reduction in the thresholds for thirst and arginine vasopressin secretion coupled with a substantial increase in placental clearance of arginine vasopressin. Reversal of these changes after delivery results in normalization of the disordered water homeostasis, with consequent resolution of the diabetes insipidus.

Pituitary function after selective adenomectomy for Cushing's disease.

This retrospective analysis was undertaken to determine whether selective adenomectomy for Cushing's disease can achieve acceptable cure rates while causing minimal pituitary dysfunction. Tumour size, histology and pituitary function were evaluated in 34 consecutive patients (26 F: 8 M, mean age 33.6 years) undergoing transphenoidal adenomectomy for Cushing's disease from 1975 to 1992. Follow-up averaged 5.8 years. Cure was defined as resolution of symptoms and signs and normalization of urinary cortisol excretion. Sixty-three per cent of patients achieved cure after selective adenomectomy, repeat adenomectomy cured an additional four patients. Twenty-eight per cent required bilateral adrenalectomy and/or pituitary irradiation. Postoperative pituitary function remained completely intact in 81%. Secondary hypogonadism occurred in 8%, hypothyroidism in 155 and permanent diabetes insipidus in 4%. There was recurrence in 26% after a mean of 4.6 years (range 1-7). It is concluded that selective adenomectomy can achieve acceptable cure rates with a low prevalence of postoperative hypopituitarism, although an increase of recurrence may be the result of conservative surgery.