L. H. Rees

INCREASED β-ENDORPHIN BUT NOT MET-ENKEPHALIN LEVELS IN HUMAN CEREBROSPINAL FLUID AFTER ACUPUNCTURE FOR RECURRENT PAIN

Low-frequency electroacupuncture effectively alleviated recurrent pain in 10 patients. Basal levels of beta-endorphin and met-enkephalin in the lumbar cerebrospinal fluid (CSF) of these patients were not different from those in pain-free control subjects. After electroacupuncture in the patients with pain CSF beta-endorphin levels rose significantly in all subjects, but met-enkephalin levels were unchanged. These results suggest that the analgesia observed after electroacupuncture in patients with recurrent pain may be mediated by the release into the CSF of the endogenous opiate, beta-endorphin.

Cyclical combination chemotherapy and gonadal function. Retrospective study in males.

The effect of cyclical chemotherapy on fertility and gonadal function was investigated in seventy-four male patients who had been treated for advanced Hodgkins disease. All patients were azoospermic after therapy, and, with a median follow-up period of 27 months (range 1--62 months), only four patients have regained spermatogenesis. Testicular biopsy showed an absence of germinal epithelium without other gross architectural changes. Despite this high degree of infertility, 60% of patients were practising contraception. A decline in libido and sexual performance with frequent long periods of sexual inactivity was noted by most men during therapy. Although some recovery was apparent once therapy was stopped, this was incomplete in approximately half of the patients. Follicle-stimulating-hormone levels were consistently raised after therapy at all periods of study. Median luteinising-hormone levels were at, or just above, the upper limit of normal, and median testosterone levels were normal. Increased prolactin levels were noted in 42% of patients, of whom about a half had an identifiable cause for hyperprolactinaemia. Return of spermatogenesis could not be predicted by serial hormone assessment. Because of the guaranteed infertility and the low frequency and unpredictability of recovery of spermatogenesis, sperm storage should be available for male patients undergoing cytotoxic therapy, since most of these patients may enjoy prolonged survival. Hormone-replacement therapy will usually be unnecessary. However, the probability of major changes in libido and sexual performance should be discussed with patients so that additional stress can be avoided. Contraceptive advice should be available to those who require it.

ACUPUNCTURE IN HEROIN ADDICTS: CHANGES IN MET-ENKEPHALIN AND β-ENDORPHIN IN BLOOD AND CEREBROSPINAL FLUID

In heroin addicts showing features of heroin withdrawal basal beta-endorphin levels were elevated in both blood and cerebrospinal fluid (CSF) and did not change during electroacupuncture, although this therapy suppressed the clinical features of withdrawal. Met-enkephalin levels were not elevated in blood or CSF before treatment. However, successful electroacupuncture was associated with a rise in CSF met-enkephalin levels in all patients studied, although concentrations in blood did not alter.

β-ENDORPHIN IN HUMAN CEREBROSPINAL FLUID

beta-endorphin is a brain peptide with potent morphine-like activity structurally related to the anterior pituitary hormone beta-lipotrophin (beta-L.P.H.). We have developed a radioimmunoassay for human beta-endorphin in plasma and cerebrospinal fluid (C.S.F.). Since the antiserum also reacts with beta-L.P.H., beta-endorphin was distinguished by using a second antiserum which measures beta-L.P.H. alone. With these two immunoassay systems and gel chromatography, we found beta-endorphin in all 20 C.S.F. samples tested at a concentration always higher than, but with no other relationship to, that in plasma. beta-endorphin was found in C.S.F. of patients who had hypopituitarism and undetectable plasma-beta-endorphin, suggesting that it is synthesized in the brain rather in the pituitary.

CRF IN THE DIFFERENTIAL DIAGNOSIS OF CUSHING'S SYNDROME: A COMPARISON WITH THE DEXAMETHASONE SUPPRESSION TEST

Accurate differential diagnosis of the precise cause of Cushings syndrome can be difficult, and conventional tests such as those based on the use of dexamethasone may be misleading. We have therefore studied the cortisol and ACTH responses to ovine corticotrophin‐releasing factor (CRF‐41) in 28 consecutive patients with Cushings syndrome, and compared the diagnostic value of this test with that of the high‐dose dexamethasone suppression test (8 mg/day for 48 h).

Megavoltage pituitary irradiation in the management of prolactinomas : long-term follow-up

objective To determine the long‐term effects of external beam megavoltage radiotherapy (RT: 4500 cGy via three portals at 180 cGy or less total daily dose) on endocrine function in prolactinomas.

Alpha-Adrenergic Stimulation of Corticotropin Secretion by a Specific Central Mechanism in Man

In a double-blind study in normal subjects, methoxamine, a highly selective agonist at alpha-1-adrenoceptors, significantly increased circulating ACTH and cortisol. The stimulant effect of methoxamine on cortisol secretion was dose dependent in the range 3.5-7 micrograms/kg/min, was abolished by concomitant administration of the strong alpha-1-adrenergic (and weak H1) antagonist thymoxamine but unaffected by the antihistamine, chlorpheniramine. In order to test whether the action of methoxamine on ACTH secretion was exerted centrally or peripherally, the effects of norepinephrine (NE), an alpha-1-agonist that does not cross the blood-brain barrier, were studied. Doses of NE (1-12 micrograms/min) that increased systolic blood pressure by amounts similar to the changes produced by methoxamine, did not result in any rise in plasma cortisol in normal subjects. The effect of methoxamine, which is more lipid soluble than NE, on plasma ACTH and cortisol, appears to be exerted on the CNS and not at the pituitary or via nonspecific peripheral mechanisms. In addition to its water solubility, NE differs from methoxamine in its beta-1-, beta-2- and alpha-2-agonist actions. However, prenalterol (2 mg) and salbutamol (250 micrograms), respectively beta-1- and beta-2-adrenergic agonist drugs, had no effect on the secretion of ACTH or cortisol and the alpha-2-antagonist yohimbine in an effective dose did not unmask a stimulant effect of intravenous NE on plasma cortisol. At high infusion rates, NE significantly inhibited cortisol secretion. Stimulation of central alpha-1-adrenergic mechanisms results in secretion of ACTH in man, presumably by increased release of a corticotropin-releasing factor.

Treatment of growth-hormone deficiency with growth-hormone-releasing hormone

18 prepubertal growth-hormone (GH)-deficient children were treated with twice-daily subcutaneous injections of a growth-hormone-releasing hormone analogue, GHRH (1-29) NH2. In 12 of the children the height velocity rose on GHRH treatment, and 8 were judged to have shown a worthwhile response to therapy in that their height velocities during the first 6 months of treatment increased by greater than 2 cm/yr (range 2.7-11.2 cm/yr). These 8 children have now been treated for 6 to 18 months and their increase in height velocity has been maintained. In the 14 patients who had previously received human GH (hGH) height velocity on hGH correlated with that on GHRH. 4 of these patients showed growth deceleration with GHRH, for unknown reasons. A pretreatment peak serum GH response of above 30 mU/l during an intravenous GHRH test was predictive of a good growth response to GHRH but a lower peak did not preclude a growth response. There was no consistent evidence of a priming or desensitisation effect of therapy on the GH responses to GHRH. Although anti-GHRH antibodies developed in 14 patients, these did not seem to have adverse effects on either growth or the GH responses to GHRH. GHRH (1-29) NH2 therapy is an alternative to conventional hGH in the treatment of some GH-deficient children. Ideal dose regimens need to be established.

Neuropeptide-Y stimulates CRF-41 release from rat hypothalami in vitro.

There is increasing evidence that neuropeptide-Y (NPY) exerts a stimulatory effect on the hypothalamo-pituitary-adrenal axis. Although it has been suggested that this stimulatory effect may be mediated via an action on hypothalamic CRF-41 release, direct measurements have not previously been made. In this study, the direct effect of NPY on hypothalamic CRF-41 secretion has been investigated in vitro using acute hypothalamic explants and previously described incubation techniques. NPY in the concentration range 10(-8)-10(-5) M produced a dose-dependent stimulation of CRF-41 release which was maximum at a concentration of 10(-6) M. The possibility that this stimulatory effect might reflect an interaction with noradrenergic inputs to CRF-41 neurons was excluded by incubating the hypothalami in the presence of NPY in combination with either the beta-adrenoceptor antagonist, propranolol (10(-5) M), or the alpha 1-adrenoceptor antagonist, prazosin (10(-5) M); neither inhibited NPY-stimulated CRF-41 release, suggesting that this effect is unrelated to noradrenergic pathways and is exerted through distinct receptor mechanisms. Furthermore, norepinephrine-stimulated (10(-8)-10(-6) M) CRF-41 release was not potentiated in the presence of NPY (10(-6) M). In summary, these data provide evidence for a direct stimulatory effect of NPY on CRF-41 secretion from the rat hypothalamus in vitro. This effect is independent of catecholaminergic interactions, suggesting that it is mediated either directly on CRF-41 neurons or through non-catecholaminergic neuronal systems.

CORTICOTROPIN-RELEASING FACTOR IMMUNOREACTIVITY IN HUMAN GASTROINTESTINAL TRACT

Abstract An antiserum to the 41-aminoacid residue ovine corticotropin-releasing factor (CRF-41) and an immunohistochemical technique were used to demonstrate the presence of CRF-41 immunoreactivity in the human gastrointestinal tract as well as in the hypothalamus. Distinct CRF-41 immunoreactivity was found in numerous mucosal cells of the gastric antrum but in only a few mucosal cells of the small intestine. These apparent gut CFR-41 cells may have both paracrine and endocrine functions.