A. Grossman

Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment

OBJECTIVE We tested the hypothesis that in Cushings disease, ACTH secretion from the normal pituitary surrounding an ACTH‐secreting adenoma is inhibited and hence removal of the entire adenoma should result in an undetectable serum cortisol in the immediate post‐operative period.

Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure

OBJECTIVEu2003Previous studies of surgical treatment for acromegaly have used varied criteria for ‘cure’, but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer‐term outcome for patients not offered further treatment when post‐operative levels of GHu2003<u20035u2003mU/l were achieved.

THE OPIOID CONTROL OF LH AND FSH RELEASE: EFFECTS OF A MET‐ENKEPHALIN ANALOGUE AND NALOXONE

The effect of a long‐acting analogue of met‐enkephalin (DAMME) and naloxone on gonadotrophin secretion has been investigated in man. In menopausal women DAMME induced a progressive fall in LH to approximately 60% of basal levels at 3 h, which was blocked by naloxone; there was a smaller fall in FSH that did not attain statistical significance. However, the LHRH‐induced rise in LH and FSH in young male volunteers was unaffected by pretreatment with a high‐dose DAMME infusion. Naloxone infusion in young male and female normal subjects produced a significant rise in both LH and FSH. Long‐term infusion of naloxone appeared to increase the rate, and possibly the amplitude, of LH pulsatility. These results suggest that met‐enkephalin‐like opioid peptides exert a tonic inhibitory control of LH release in both menopausal and young subjects of both sexes. This control is most likely to be at the level of the hypothalamus, and involves modulation of pulsatile LHRH release.

CORTICOTROPHIN RELEASING FACTOR: RESPONSES IN NORMAL SUBJECTS AND PATIENTS WITH DISORDERS OF THE HYPOTHALAMUS AND PITUITARY

Synthetic CRF‐41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (± SE) was 276 ± 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r= ‐0·56; P<0·02). The mean peak serum cortisol was 662 ± 34 nmol/1 and the mean peak corticosterone was 28·6 ± 3·8 nmol/1. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r= 0·84; P<0·0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF‐41. The peak serum cortisol following CRF‐41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin‐induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 μg of CRF‐41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF‐41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary‐dependent Cushings disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF‐41. These normal or enhanced responses of hypercortisolaemic patients with Cushings syndrome contrast with the complete inhibition of the responses to CRF‐41 in normal subjects given dexamethasone. In the treated patients with Cushings syndrome

GH FEEDBACK OCCURS THROUGH MODULATION OF HYPOTHALAMIC SOMATOSTATIN UNDER CHOLINERGIC CONTROL: STUDIES WITH PYRIDOSTIGMINE AND GHRH

We have studied the effect of increased cholinergic tone on the GH response to growth hormone‐releasing hormone (GHRH) and on GH feedback, using pyridostigmine, an acetylcholinesterase inhibitor. In six healthy male adult volunteers 120 mg oral pyridostigmine increased basal GH secretion compared to placebo and augmented the GH response to 100 μg i.v. GHRH (1‐29) NH2; the effect was more than the additive effect of pyridostigmine and GHRH when each was given alone. Pretreatment with 2 IU methionyl‐hGH given i.v. abolished the serum GH response to GHRH given 3 h later, demonstrating a negative feedback loop of GH on the response to GHRH; this inhibited response to GHRH was restored in subjects given pyridostigmine as well as methionyl‐hGH. The data demonstrate that enhanced cholinergic tone releases GH, augments the serum GH response to GHRH and unblocks the negative feedback effect of methionyl‐hGH pretreatment on the GH response to GHRH. These results suggest that GH negative feedback effects on its own secretion occur predominantly through increased hypothalamic somatostatin secretion; this somatostatin secretion is under inhibitory cholinergic control.

STUDIES ON CIRCULATING MET-ENKEPHALIN AND β-ENDORPHIN: NORMAL SUBJECTS AND PATIENTS WITH RENAL AND ADRENAL DISEASE

Studies were performed to define the responses of plasma met‐enkephalin to various endocrine and pathological stimuli and to determine the relationship between plasma β‐endorphin and met‐enkephalin. During insulin‐induced hypoglycaemia ACTH, β‐LPH and β‐endorphin immunoreactivity rose in parallel, but plasma met‐enkephalin did not change significantly. Sephadex G75 chromatography of samples taken at the time of the peak response (45 min) confirmed the rise in both β‐LPH and β‐endorphin. During administration of dexamethasone, 0·5mg 6 hourly for 48 h, plasma cortisol and ACTH became undetectable at 24 h, and β‐LPH and β‐endorphin fell significantly by 24 h and were undetectable by 48 h; plasma met‐enkephalin, however, showed no significant change. Nine adrenalectomized patients with Cushings disease and four patients with Addisons disease had elevated plasma ACTH, β‐LPH and β‐endorphin but normal plasma met‐enkephalin levels. Each of ten patients with renal failure had markedly elevated plasma met‐enkephalin immunoreactivity which co‐eluted with synthetic met‐enkephalin on BioGel P4 chromatography. Trypsin and carboxypeptidase‐B digestion of the P4 chromatography fractions generated met‐enkephalin immunoreactivity in earlier fractions, indicating the presence of a potential high molecular weight met‐enkephalin precursor.

Opiate mediation of amenorrhoea in hyperprolactinaemia and in weight-loss related amenorrhoea.

Endogenous opiates are involved in the control of pituitary gonadotrophin and PRL secretion, and possibly of food intake. Both hyperprolactinaemia and weight loss (especially in anorexia nervosa) are frequently associated with amenorrhoea and an absence of gonadotrophin pulsatility. Since it has been suggested that increased endogenous opiate tone may operate in both conditions, we infused high‐doses of naloxone into twelve patients with amenorrhoea of whom five had hyperprolactinaemia and seven had weight‐loss related amenorrhoea. Eleven of the twelve patients had low levels of oestradiol (< 50 pmol/l). Naloxone induced a marked rise in both LH and FSH levels in all of the five hyperprolactinaemic patients. In contrast, the patients with weight‐loss amenorrhoea responded to naloxone with only a small or no rise in gonadotrophins. There was no consistent change in PRL in either group of patients. It is concluded that in hyperprolactinaemia, but not weight‐loss amenorrhoea, there is an important endogenous opiate‐mediated tonic inhibition of secretion of hypothalamic gonadotrophin releasing hormone.

Brain opiates and neuroendocrine function

Opioid peptides are found throughout the central nervous system, and have profound effects on neuroendocrine function. In man, exogenous opiates and opioids elevate circulating prolactin, GH and TSH, and suppress the release of the gonadotrophins and pro-opiocortin-related peptides. However, unlike in other species, there is substantial evidence for a physiological role of endogenous opioids only in the case of the gonadotrophins and ACTH/LPH. Most evidence suggests that LH and FSH are modulated via the hypothalamus or amygdala, where concentrations of opioids and opioid receptors are very high. Endogenous opioids appear to be principally concerned with the frequency-modulated release of GnRH, and this may be important clinically in patients presenting with amenorrhoea. ACTH/LPH are under tonic inhibition by endogenous opioids acting at hypothalamic and/or pituitary levels, and changes in this inhibition may be responsible for the release of these peptides in response to certain forms of stress. It has been reported that the opiate antagonist, naloxone, is clinically useful in paradoxically inhibiting the release of ACTH in patients with Nelsons syndrome, but this requires adequate confirmation. Vasopressin is under biphasic opiate control, but the principal effect is probably opiate-mediated inhibition of vasopressin release. The endogenous ligand for this response is likely to be dynorphin. Suppression of vasopressin release by opiates may become a useful therapy in the treatment of the Syndrome of inappropriate ADH.

OPIATE MODULATION OF THE PITUITARY-ADRENAL AXIS: EFFECTS OF STRESS AND CIRCADIAN RHYTHM

The opiate control of the pituitary‐adrenal axis has been investigated in normal subjects. The infusion of 1 mg of the met‐enkephalin analogue, DAMME, led to a fall in circulating cortisol in spite of a fall in blood pressure. Conversely, 16 mg of the opiate antagonist, naloxone led to brisk and pronounced elevations in plasma ACTH, lipotrophin (LPH) and cortisol. The rise above basal levels was consistent, irrespective of whether the infusion was given at 09.00, 18.00, or 23.00 h; the peak response obtained was significantly less at 23.00 h than at either 09.00 or 18.00 h. Finally, insulin‐induced hypoglycaemia (0.15 u/kg) or naloxone (25 mg) produced a similar rise in plasma cortisol which was no different when the two stimuli were combined.

OPIATES CONTROL ACTH THROUGH A NORADRENERGIC MECHANISM

The administration of 16 mg of naloxone to six normal male subjects produced a significant rise in plasma cortisol. Pre‐treatment with the noradrenergic α1‐antagonist, thymoxamine 0.2 mg/kg, blocked this rise. It is suggested that opiate inhibition of the pituitary—adrenal axis is mediated via a noradrenergic pathway.