Sleep apnoea: clinical importance and facilities for investigation and treatment in the UK. Addendum to the 1993 Royal College of Physicians Sleep Apnoea report.

The potential importance of the obstructive sleep apnoea syndrome (OSA) has been recognized only in the last few years. Epidemiological studies suggest that symptomatic OSA occurs in 1-2% of middle-aged men and in approximately half that number of women. The relation of OSA to vascular disease is uncertain and the main indication for treatment is the relief of disabling sleepiness. Two recent evidence based analyses have produced diametrically opposed conclusions on the efficacy of treatment with nasal continuous positive airway pressure (CPAP). However, recent controlled studies confirm the overwhelming clinical experience of benefit. Facilities for the investigation and treatment of patients with OSA in the UK are subject to severe financial constraints and the availability of CPAP treatment lags markedly behind that in other countries for which data are available.

ACTH precursors characterize the ectopic ACTH syndrome.

OBJECTIVE: ACTH is secreted by the pituitary following processing of larger molecular weight precursors, proopiomelanocortin and pro-ACTH. Ectopic ACTH syndrome refers to the secretion of ACTH by non-pituitary tumours, but the predominant circulating form of proopiomelanocortin-related peptides remains unclear. PATIENTS: Fifteen patients with ectopic ACTH syndrome were compared to 20 patients with pituitary-dependent Cushing's syndrome, 22 patients with small cell lung carcinoma but no evidence of Cushing's syndrome, and 25 controls. DESIGN AND MEASUREMENTS: Measurement of plasma ACTH and ACTH precursors using specific monoclonal-based immunoradiometric assays at 0900 h and, in five patients with ectopic ACTH syndrome, at 15-minute intervals for 6-24 hours. RESULTS: ACTH precursors were grossly elevated in patients with ectopic ACTH syndrome (median 2194, range 139-18000 pmol/l) compared to patients with Cushing's disease (median 33, 8-73 pmol/l, P < 0.001), patients with small cell lung carcinomas (38, 8-117 pmol/l, P < 0.001) and controls (26, 10-39 pmol/l, P < 0.001). ACTH levels were also elevated in ectopic ACTH syndrome (0900 h median 34, 11-152 pmol/l) compared to patients with Cushing's disease (0900 h median 8, 3-19 pmol/l), but not to the same degree as ACTH precursors. In contrast with Cushing's disease, ACTH was secreted in a non-pulsatile fashion. ACTH precursors but not ACTH itself correlated with plasma cortisol in patients with ectopic ACTH syndrome (r = 0.65, P < 0.05). Chromatographic analysis of plasma from a patient with ectopic ACTH syndrome confirmed ACTH precursors and not ACTH to be the predominant circulating form. With the cross-reactivity of proopiomelanocortin and pro-ACTH in the ACTH IRMA of < 1 and < 10% respectively, ACTH precursors could represent all the ACTH immunoreactivity in patients with ectopic ACTH syndrome. CONCLUSIONS: Ectopic 'ACTH' is characterized by aberrant processing of proopiomelanocortin and should be more accurately referred to as 'ectopic ACTH precursor syndrome'.

The hypothalamo-pituitary-adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome.

OBJECTIVE: We explored the hypothesis that activation of the hypothalamo-pituitary-adrenal axis is involved in the pathogenesis of hyperandrogenism in the polycystic ovary syndrome. PATIENTS: Seven women with polycystic ovary syndrome (mean age 27.6 +/- 1.6 (SEM) years) (hirsutism, oligo/amenorrhoea and elevated serum testosterone and dehydroepiandrosterone sulphate) and nine normal female controls (mean age 24.6 +/- 1.5 years) were studied. To exclude anovulation as a confounding factor, four of these normal women were studied in both the follicular and luteal phase of the menstrual cycle. DESIGN AND MEASUREMENTS: Plasma ACTH and cortisol levels were measured at 15-minute intervals between 0600 h and 1800 h. ACTH and cortisol mean levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and cortisol peaks. RESULTS: With the exception of mean plasma levels of ACTH over the 12-hour period, which were reduced in the luteal phase of the menstrual cycle (1.8 +/- 0.3 pmol/l) compared to the follicular phase (2.3 +/- 0.2 pmol/l, P < 0.05), there were no differences in the pattern of ACTH or cortisol secretion across the normal cycle. In polycystic ovary syndrome, 12-hour ACTH pulse frequency was reduced (3.6 +/- 0.7) compared with controls (5.9 +/- 0.6, P < 0.05), but cortisol pulsatility and ACTH and cortisol mean levels were similar in both groups. CONCLUSION: The hyperandrogenism of polycystic ovary syndrome cannot be explained by enhanced ACTH secretion. Normal circulating cortisol levels, yet elevated dehydroepiandrosterone sulphate levels, suggests that polycystic ovary syndrome is yet another example of discrepant adrenal glucocorticoid and androgen secretion, and provides further evidence for a putative adrenal androgen stimulating factor.

Phaeochromocytomas as a cause of hypotension.

A patient presented with apparent septicaemic shock. Full invasive cardiovascular monitoring revealed systemic hypotension, high normal cardiac output, and a low systemic vascular resistance. Maintenance of systemic vascular resistance and blood pressure was shown to be highly dependent on noradrenaline. Subsequent investigation revealed the presence of a phaeochromocytoma producing adrenaline. The mechanisms by which phaeochromocytomas may produce hypotension are discussed.

Growth hormone secreting pituitary carcinoma: a case report and literature review.

Only five cases of growth hormone secreting pituitary carcinoma have been documented. We present a 49-year-old West Indian male with grossly elevated plasma growth hormone (760-10,400 mU/l), and a large aggressive pituitary tumour that continued to grow despite repeated pituitary surgery, radiotherapy and medical therapy (bromocriptine and somatostatin analogue). Thirteen years after diagnosis the patient died secondary to left ventricular failure. A post-mortem revealed a large locally invasive pituitary tumour, but in addition numerous tumour seedlings within the cerebrospinal fluid space, and a solitary intraparenchymal tumour deposit within the right temporal lobe, clearly separate from the primary tumour. Pituitary carcinoma should be considered in any acromegalic with grossly elevated plasma growth hormone levels who fails to respond to conventional therapy.

Hypothalamic abnormalities in patients with pituitary-dependent Cushing's syndrome.

OBJECTIVE: We aimed to investigate the pattern of 24-hour ACTH and cortisol secretion in pituitary-dependent Cushing's syndrome and to evaluate the pituitary and hypothalamic contributions to the disease. PATIENTS: Five women with Cushing's disease (mean age 35 +/- 5 (SEM) years) and five normal female controls (mean age 25 +/- 2 years) were studied. DESIGN AND MEASUREMENTS: Plasma ACTH and cortisol levels were measured every 15 minutes for 24 hours using established IRMA and RIA respectively. ACTH and cortisol mean and trough levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and cortisol peaks. RESULTS: Patients with Cushing's disease had a twofold increase in 24-hour mean cortisol levels and a threefold increase in 24-hour mean ACTH levels (Cushing's 5.9 +/- 1.0, controls 1.9 +/- 0.2 pmol/l, P less than 0.01). This was predominantly mediated by an increase in ACTH pulse amplitude. However, 24-hour ACTH pulse number was also increased (Cushing's 15.2 +/- 2.6, controls 10.6 +/- 1.7, P less than 0.05) due to an increase in pulse number between 1800 and 2400 h. ACTH trough levels were also higher in patients with Cushing's disease (Cushing's 5.3 +/- 1.3, controls 2.3 +/- 0.2 pmol/l, P less than 0.05). CONCLUSIONS: Twenty-four-hour mean plasma cortisol and ACTH levels are elevated two to three-fold in patients with Cushing's disease. The increase in ACTH pulse amplitude suggests a pituitary abnormality in patients with Cushing's disease. However, the increased ACTH pulse frequency together with elevated trough levels is interpreted as indicating coexisting hypothalamic stimulation (or loss of inhibition).

Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females.

Patterns of plasma ACTH and cortisol concentrations were studied in 10 healthy subjects (five male, five female in the early follicular phase, overall age range 21-32 years) by sampling through an indwelling cannula every 15 min for 24 h. The subjects were in hospital, ambulant, and taking normal meals. Plasma ACTH was measured by a two-site immunoradiometric assay with a detection limit of 3.9 ng/l (0.9 pmol/l). Pulses were identified by the method of Clayton et al. (1987) using stringent criteria to minimize false positive peaks. All subjects showed a circadian rhythm of ACTH, the acrophase occurring between 0615 and 0920 h in all but one subject and the mesor value was between 9.2 and 18.6 ng/l (2.0 and 4.1 pmol/l). There were significantly fewer pulses between 1800 and 2400 h compared with the other three 6-h periods. The pattern of ACTH differed between males and females in several respects: more pulses (18 vs 10), greater mean peak amplitude (16.8 vs 10.3 ng/l), greater area under the 24-h profile (350.9 vs 206.6 ng/l h) and higher mean level (14.7 vs 8.6 ng/l) in the males. In contrast, the cortisol pattern did not show statistically different sex differences. The sex differences suggest greater sensitivity to, or availability of, ACTH to the female adrenal cortex, or different set points in cortisol feedback.

Regulation of LH subunit and prolactin mRNA by gonadal hormones in mice.

The effect of castration and gonadal steroid replacement on the concentrations of LH-beta and alpha subunit and prolactin mRNA was examined in mice. Mouse LH-beta, alpha and prolactin mRNAs were approximately 0.8, 0.7 and 1.1 kb in size respectively. After ovariectomy, LH-beta mRNA levels increased 2- to 2.5-fold, while alpha mRNA levels increased 2.5-fold 6 and 10 days after ovariectomy. Serum LH rose after 2 days to reach six times control values at 10 days. Pituitary LH content doubled by 8 days after ovariectomy. Prolactin mRNA levels decreased to 50-60% of control at 3, 6, 8 and 10 days after ovariectomy and parallelled the fall in serum prolactin. Pituitary prolactin content fell more slowly, to 50% of intact control values by 10 days. The increase in both LH-beta and alpha subunit mRNA, and decrease in prolactin mRNA, and serum and pituitary hormone changes, after ovariectomy were prevented by oestradiol or oestradiol plus progesterone replacement. Levels of LH-beta mRNA increased more quickly in male than in female mice, the earliest change being seen 24 h after orchidectomy. Maximum values (two- to threefold) were found on day 6 after orchidectomy. Concentrations of alpha mRNA increased by 12 h to between 2 and 2.5 times control from 3 to 10 days after orchidectomy. Serum LH doubled by 12 h and was three to five times greater than control values up to 10 days. Pituitary LH content fell by 48 h before gradually increasing to intact values after 10 days. Prolactin mRNA levels decreased progressively from 2 days after orchidectomy, and this decrease was preceded by a fall in serum and pituitary prolactin which remained low throughout the experiment. Testosterone treatment attenuated the rise in alpha mRNA, prevented the rise in LH-beta mRNA and serum LH and partially restored the decrease in prolactin mRNA seen after orchidectomy. We conclude that in mice, as in rats and ewes, both LH-beta and alpha subunit mRNAs are negatively regulated by gonadal steroids, whereas prolactin mRNA is positively regulated, although there are temporal differences in patterns of mRNA responses between males and females. By comparison with female rats the rise in LH-beta mRNA after ovariectomy was slower in mice. Moreover, the discordant changes in pituitary LH content and LH subunit mRNAs seen in mice after castration were not observed in rats. Furthermore, pituitary prolactin and prolactin mRNA do not fall after orchidectomy of rats.(ABSTRACT TRUNCATED AT 400 WORDS)

The interaction of gonadotropin-releasing hormone and estradiol on luteinizing hormone and prolactin gene expression in female hypogonadal (hpg) mice.

We have investigated the interaction of estrogen with GnRH on the regulation of LH subunit mRNA in female hypogonadal (hpg) mice receiving constant frequency and amplitude pulsatile GnRH treatment for up to 18 days. The level of cytosolic common alpha mRNA in female hpg mouse pituitaries was 45 +/- 6% of normal female littermate values, and treatment with pulsatile GnRH increased alpha mRNA to 40% above the normal value at 24 h and 2-4 times normal at 7 and 12 days (P less than 0.001); by 18 days levels had returned to those of untreated hpg controls. Concurrent treatment with estradiol (E2) did not affect those changes. However, in ovariectomized hpg mice the 2- to 4-fold rise in alpha mRNA was sustained for 18 days with GnRH treatment. E2 treatment alone for 7 and 12 days doubled alpha mRNA. LH beta mRNA levels in untreated female hpg mice were between 5-10% of normal values. Levels increased significantly (77 +/- 6.4%) 24 h after GnRH treatment and were normal at 7, 12, and 18 days. E2 together with GnRH did not affect the LH beta mRNA increase at 12 days, but reduced it to 45% of normal at 18 days. Ovariectomy did not alter the LH beta mRNA response to GnRH treatment, and E2 treatment alone did not increase LH beta mRNA. Serum LH concentrations were normalized by GnRH treatment at all times and did not increase in ovariectomized animals. LH release was prevented when E2 was combined with GnRH. Pituitary LH content in hpg mice was 20% of normal and increased gradually with GnRH treatment. Neither concurrent treatment with E2 nor ovariectomy affected the GnRH-induced synthesis of LH. PRL mRNA levels were 30-40% of normal littermate values in untreated female hpg mice, and pulsatile GnRH increased these to 70-80% of normal. E2 alone raised PRL mRNA slightly above normal values, although together with GnRH this rise was attenuated by about 40%. Pulsatile GnRH treatment of ovariectomized hpg mice did not increase PRL mRNA. E2 increased pituitary PRL content, and GnRH did not attenuate this aspect of E2 action. Serum PRL levels rose with E2 treatment at 7 and 12 days, and concurrent GnRH treatment prevented the rise at 12 days. We conclude the following: 1) The stimulatory action of pulsatile GnRH on the expression of both common alpha and LH beta mRNA is rapid (less than 24 h).(ABSTRACT TRUNCATED AT 400 WORDS)

DNA and RNA analysis of cytochrome P-450 21-hydroxylase: transcriptional activity in congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a family of inherited disorders of adrenal steroidogenesis, most commonly due to deficiency of P-450 21-hydroxylase (21-OH). There are two genes for 21-OH on the short arm of chromosome 6, the A gene which is thought to be inactive, and the B gene. These genes appear as 3.2 and 3.7 kb TaqI fragments on Southern blots. In a study of DNA from 60 normal controls with TaqI and a 21-OH cDNA probe, 12% exhibited a homozygous deletion of the A gene, and 22 and 8% heterozygous deletions of A and B genes respectively. TaqI analysis of eight patients with CAH revealed four without A or B gene deletions, three with heterozygous deletions of the B gene and one with a homozygous deletion of the B gene. On further analysis with KpnI, EcoRI, PvuII and BglII, however, these genotypes were amended to two with heterozygous deletions of the B gene and two with possible B to A gene conversions. The genotypes of the four patients without deletions remained unchanged. RNA from CAH and Cushing's adrenal tissue was also analysed using A and B gene-specific oligodeoxynucleotide probes. B gene transcripts were detected in both CAH and Cushing's adrenals, while no A gene transcripts could be detected in either tissue. The level of B gene-derived mRNA was greater in the Cushing's adrenal than in the CAH adrenal, which in turn was greater than that in the adrenal from a normal individual.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of long term dexamethasone treatment in adult patients with congenital adrenal hyperplasia.

We have followed nine adult patients with congenital adrenal hyperplasia (CAH) for between 7-77 months on dexamethasone (DXM) 0.5 mg mane and 0.25 mg nocte, reducing to 0.5 mg mane. Twenty-four hour profiles of ACTH, 17-hydroxyprogesterone (17OHP), and androstenedione were performed; the areas under the curves (AUC) and the heights of the morning peaks were used to assess biochemical control. Comparisons were made between treatment before DXM (pre-DXM), 0.75 mg for 2 weeks (DXM-ST), 0.75 mg for at least 3 months (DXM-LT), and 0.5 mg for at least 3 months (DXM-0.5). None of the three males suffered any significant side-effects. All women had menstrual disturbance but in three ovulation was induced. One female developed Cushing's syndrome and two developed hirsutism which resolved on stopping DXM. Overall there was no significant difference between DXM-ST and DXM-LT (mean AUCs for ACTH: DXM-ST 660, DXM-LT 383, for 17OHP: DXM-ST 1177, DXM-LT 587, for androstenedione DXM-ST 232, DXM-LT 121). Reduction of the dose from 0.75 mg to 0.5 mg led to significant deterioration in control (Mean AUC's for ACTH DXM-0.5, 1123 (P less than 0.02), for 17OHP DXM-0.5, 2068 (P less than 0.002), for androstenedione DXM-0.5, 213 (P less than 0.5). We conclude that DXM is a satisfactory regime but the dose must be adjusted for each patient.

Effect of oestrogen treatment on gonadotroph function in adult male rats.

The effect of oestradiol-17 beta on the hypothalamo-pituitary axis of intact adult male rats was studied. A single injection of oestradiol did not change the serum LH response to gonadotrophin-releasing hormone (GnRH) 48 h or 7 days after the injection, while administration of oestrogen over 66 days suppressed basal serum LH to less than 3.1 micrograms/l and did not enhance the LH response to GnRH at any time. Treatment of ovariectomized rats with oestradiol capsules, however, enhanced the LH response to GnRH on days 3 and 14 of the treatment as compared with the control group (P less than 0.02 and P less than 0.05 respectively). Long-term treatment with oestradiol suppressed intrapituitary LH and FSH contents as well as pituitary GnRH receptors (P less than 0.0004, P less than 0.005 and P less than 0.001 respectively), whereas serum and intrapituitary prolactin levels were increased. To exclude the possible lactin levels were increased. To exclude the possible inhibitory effect of hyperprolactinaemia on LH were treated with bromocriptine. This prevented the rise in serum prolactin, but failed to enhance the LH response to GnRH. Neither short- nor long-term treatment with oestradiol given under conditions shown to be effective in female animals stimulated the hypothalamo-pituitary-gonadotrophin axis in adult male rats.

Prolactin and growth hormone dynamics in epileptic patients receiving phenytoin.

Resting growth hormone and prolactin levels and dynamic responses to bromocriptine and metoclopramide have been measured in epileptic patients before treatment, and compared with a matched group taking phenytoin alone. Mean resting levels of prolactin were higher in patients taking phenytoin (untreated patients 204 mU/l, phenytoin treated patients 302 mU/l), but dynamic responses to metoclopramide and bromocriptine were unaffected. Mean resting levels of growth hormone were also higher in patients taking phenytoin (untreated patients 1.4 mU/l, phenytoin treated patients 6.0 mU/l) and paradoxical suppression was seen following bromocriptine. Phenytoin is unlikely to have any major action on the D2 receptor present on the lactotroph. The abnormalities in growth hormone may explain the well recognized effects of phenytoin on connective tissue.

The feminisation of gonadotrophin responses in intact male transsexuals.

In castrated animals and hypogonadal men other workers have shown an LH surge following oestrogen administration similar to that found in the normal female. However, there is no evidence that this can be achieved in intact males. We have therefore studied male transsexual patients before and after chronic oestrogen therapy given for at least three months to feminise the body habitus before undergoing plastic surgery. Subjects were assessed for the acute effects of oestradiol valerate on sex steroid hormone levels and gonadotrophin responses to gonadotrophin releasing hormone. The results showed that longterm treatment could transform the normal male pattern of a suppressive effect of oestrogen on gonadotrophin release to one where the oestrogen increased LH levels and amplified the effect of LHRH on gonadotrophin release. This pattern is similar to that found in normal women and indicates that longterm oestrogen treatment to males can feminise gonadotrophin responses.