Inhibition of pituitary-adrenal secretion by a corticotropin releasing hormone antagonist in humans.

Corticotropin releasing hormone (CRH) is the primary modulator of ACTH release from the pituitary, and a neuromodulator in limbic and autonomic brain regions. Dysfunction of CRH-mediated neurotransmission is emerging as a critical mechanism in several disorders. Therefore, modulation of CRH availability at receptor sites is a potentially powerful therapeutic tool. Inhibitory analogues of CRH have been tested in rodents and primates, but their safety and hormonal effects in humans are unknown. We administered a CRH-antagonist, alpha-helical-CRH-(9-41) to six individuals. Each received two intravenous infusions: 50 micrograms kg-1 on day 1, and 100 micrograms kg-1 on the following morning. These doses block both endocrine and central effects of CRH in experimental animals. ACTH, cortisol, electrolytes, glucose and autonomic parameters were monitored in comparison with control values. Infusion of CRH antagonist did not alter heart rate, blood pressure, temperature or plasma electrolytes and glucose. Pre-infusion plasma ACTH levels averaged 26.8 +/- 6.7 pg ml-1 on day 1, and 29.0 +/- 5.8 pg ml-1 on day 2. Post-infusion values were 11.8 +/- 2 and 11.5 +/- 2.4 pg ml-1, significantly lower than pre-infusion levels. Plasma cortisol levels, which averaged 21.4 +/- 4 micrograms dl-1 on the first morning and 22.9 +/- 4.2 on the second, also decreased significantly after CRH antagonist infusions (to 14.0 +/- 2.9 micrograms dl-1 on day 1, and 13.9 +/- 3.0 micrograms dl-1 on day 2). Hormonal changes were transient, and circadian rhythm was not affected. Though not measured formally, euphoria, anxiety or somnolence were not observed. In conclusion, CRH antagonist administration to adults reduces hormonal secretion by pituitary corticotrophs, with resulting decrease in plasma ACTH and cortisol

False localization of ictal activity by scalp EEG in candidates for hemispherectomy

Two patients with intractable seizures and large structural lesions were candidates for hemispherectomy for seizure control. Repeated ictal EEGs recorded from scalp falsely localized seizure onset to the contralateral hemisphere. Intracarotid amobarbital study was performed during left-body epilepsia partialis continua in one subject. Amobarbital was injected in the right internal carotid artery, despite electrographic seizure activity apparently originating in the left hemisphere. Clinical and electrographic seizure activity ceased immediately at the onset of left hemiparesis, without inducing right hemiparesis, speech loss, or EEG attenuation on the left. Intracranial recordings in both patients confirmed that the clinically suspect hemisphere was the source of the seizures, and hemispherectomy produced excellent clinical results. In the presence of a large structural lesion, it appears that scalp EEG may falsely localize ictal discharges to the contralateral side. © 1993 Butterworth-Heinemann

Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists.

Background and rationaleInfantile spasms (IS) are an age-specific seizure disorder occurring in 1:2,000 infants and associated with mental retardation in approximately 90% of affected individuals. The costs of IS in terms of loss of lifetime productivity and emotional and financial burdens on families are enormous. It is generally agreed that the seizures associated with IS respond poorly to most conventional anticonvulsants. In addition, in the majority of patients, a treatment course with high-dose corticotropin (ACTH) arrests the seizures completely within days, often without recurrence on discontinuation of the hormone. However, the severe side effects of ACTH require development of better treatments for IS. Based on the rapid, all-or-none and irreversible effects of ACTH and on the established physiological actions of this hormone, it was hypothesized that ACTH eliminated IS via an established neuroendocrine feedback mechanism involving suppression of the age-specific endogenous convulsant neuropeptide corticotropin-releasing hormone (CRH). Indeed, IS typically occur in the setting of injury or insult that activate the CNS stress system, of which CRH is a major component. CRH levels may be elevated in the IS brain, and the neuropeptide is known to cause seizures in infant rats, as well as neuronal death in brain regions involved in learning and memory. If 'excess' CRH is involved in the pathogenesis of IS, then blocking CRH receptors should eliminate both seizures and the excitotoxicity of CRH-receptor-rich neurons subserving learning and memory.Patients and methodsWith FDA approval, alpha-helical CRH, a competitive antagonist of the peptide, was given as a phase I trial to 6 infants with IS who have either failed conventional treatment or who have suffered a recurrence. The study was performed at the Clinical Research Center of the Childrens Hospital, Los Angeles. The effects of alpha-helical CRH on autonomic parameters (blood pressure, pulse, temperature, respiration) were determined. In addition, immediate and short-term effects on ACTH and cortisol and on electrolytes and glucose were examined. The potential efficacy of alpha-helical CRH for IS was studied, using clinical diaries and video EEG.Resultsalpha-Helical CRH, a peptide, did not alter autonomic or biochemical parameters. Blocking peripheral CRH receptors was evident from a transient reduction in plasma ACTH and cortisol. No evidence for the compound's penetration of the blood-brain barrier was found, since no central effects on arousal, activity or seizures and EEG patterns were observed. In addition, a striking resistance of the patients' plasma ACTH to the second infusion of alpha-helical CRH was noted.ConclusionsPeptide analogs of CRH do not cross the blood-brain barrier, and their effects on peripheral stress hormones are transient and benign. Nonpeptide compouds that reach CNS receptors are required to test the hypothesis that blocking CRH receptors may ameliorate IS and its cognitive consequences

Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms.

Infantile spasms respond to ACTH, and levels of the hormone in cerebrospinal fluid of untreated infants with this disorder were found to be lower than in age-matched controls. In this study we analyzed cerebrospinal fluid cortisol and ACTH using improved immunoassays in a larger cohort of infants with infantile spasms. Analysis of 20 patients and 15 age-matched controls revealed significantly lower levels of both ACTH and cortisol in the cerebrospinal fluid. These data, combined with the efficacy of ACTH and glucocorticoids for infantile spasms, support an involvement of the brain-adrenal-axis in this disorder

High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study.

ObjectiveTo compare the efficacy of corticotropin (ACTH) (150 U/m2/day) and prednosone (2 mg/kg/day) given for 2 weeks, in suppressing clinical spasms and hypsarrhythmic electroencephalogram (EEG) in infantile spasms (IS). AACTH and prednisone are standard treatments for IS. ACTH at high doses causes severe dose- and duration-dependent side effects, but may be superior to prednisone, based on retrospective or uncontrolled studies. Blinded prospecive studies have shown equal efficacy of prednisone and low-dose ACTH, and low versus high-dose ACTH.DesignA prospective, randomized, single-blinded study.Subjects and methodsPatient population consisted of consecutive infants fulfilling entry criteria, including the presence of clinical spasms, hypsarrhythmia (or variants) during a full sleep cycle video-EEG, and no prior steroid/ACTH treatment. Response required both cessation of spasms and elimination of hypsarrhythmia by the end of the 2-week treatment period, as determined by an investigator "blinded" to treatment. Treatment of responders was tapered off over 12 days; those failing one hormone were crossed-over to the other.ResultsOF 34 eligible infants, 29 were enrolled. Median age of patients was 6 months. Twenty-two infants were "symptomatic" with known or suspected cause, and seven were cryptogenic (two normal). Of 15 infants randomized to ACTH, 13 responded by EEG and clinical criteria (86.6%); Seizures stopped in an additional infant, but EEG remained hypsarrhythmic (considered a failure). Four of the 14 patients given prednisone responded (28.6%,, with complete clinical-EEG correlation), significantly less than with ACTH, (chi2 test).ConclusionsUsing a prospective, randomized approach, a 2-week course of high-dose ACTH is superior to 2 weeks of prednsone for treatment of IS, as assessed by both clinical and EEG criteria

Salivary Testosterone and Sexual Function and Behavior in Men and Women: Findings from the Third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3)

Using data from the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) we examined associations between salivary testosterone (Sal-T) and sexual function and behavior. Single morning saliva samples were self-collected from a subsample of participants aged 18–74 years and analyzed using mass spectrometry. 1,599 men and 2,123 women were included in the analysis (40.6% of those invited to provide a sample). We adjusted for confounders in a stepwise manner: in model 1 we adjusted for age only; model 2 for age, season and relationship status, and model 3 we added BMI and self-reported health. In the fully adjusted models, among men, Sal-T was positively associated with both partnered sex (vaginal sex and concurrent partners) and masturbation. Among women, Sal-T was positively associated with masturbation, the only association with partnered sex was with ever experience of same-sex sex. We found no clear association between Sal-T and sexual function. Our study contributes toward addressing the sparsity of data outside the laboratory on the differences between men and women in the relationship between T and sexual function and behavior. To our knowledge, this is the first population study, among men and women, using a mass spectrometry Sal-T assay to do so