VHL: Trends and Insight into a Multi-Modality, Interdisciplinary Approach for Management of Central Nervous System Hemangioblastoma.

Von Hippel-Lindau (VHL) is a multi-system disease which results in significant morbidity from central nervous system (CNS) involvement as well as ocular, renal and neuro-endocrine effects. Haemangioblastomas of the CNS present a number of challenges. The natural history of these lesions is varied, as is the size and location within the CNS. Whilst surgery is considered the mainstay of treatment and best chance at curing these lesions, this is also often associated with significant risks due to the anatomical location of these lesions, most commonly the posterior fossa and spinal cord.We review the literature and describe our experience across two separate European VHL referral centres. Alternative treatment options and combined modalities are increasingly being used in the context of managing CNS haemangioblastomas. We analyse the increasing use of stereotactic radiosurgery and the evolution of medical treatments as potential future adjuncts to surgery. The availability of multiple modalities in our armamentarium is essential in tailoring a personalised treatment approach to these patients. Owing to the multi-systemic nature of the disease, in our experience, managing the care of patients with VHL is best delivered using an interdisciplinary approach utilising multiple specialties and adopting an individually tailored holistic approach.

Male-female differences in rat hypothalamic-pituitary-adrenal axis responses to nicotine stimulation.

Hypothalamic-pituitary-adrenal (HPA) axis responsiveness differs physiologically and pharmacologically between the sexes (sexual diergism). Central nicotinic receptors modulate this endocrine axis. Previous studies have established that nicotine (NIC) stimulates the HPA axis; however, only male animals have been used. We have demonstrated that plasma arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) concentrations showed greater responsiveness in male than in female rats pretreated with scopolamine (SCOP), a muscarinic antagonist, followed by physostigmine (PHYSO), an acetylcholinesterase inhibitor. These results suggest that the SCOP + PHYSO effects may have resulted from an indirect nicotinic effect caused by increased synaptic acetylcholine with simultaneous muscarinic antagonism. In the present study, we investigated nicotinic cholinergic influences on HPA axis activity in male and female rats by administering NIC (0, 0.03, 0.1, 0.3, or 0.5 mg/kg) and determining plasma AVP, ACTH, and corticosterone (CORT) responses. Male rats had a significantly greater, dose-related AVP response to NIC than did females. In contrast, female rats had significantly greater, dose-related ACTH and CORT responses to NIC than did males. Hormone responses following NIC were similar to hormone responses following SCOP + PHYSO. These results suggest nicotinic receptors influence the HPA axis differentially in male and female rats.

Sexual diergism in rat hypothalamic-pituitary-adrenal axis responses to cholinergic stimulation and antagonism.

The hypothalamic-pituitary-adrenal (HPA) axis has differential physiological activity in male and female animals (sexual diergism). Central cholinergic systems stimulate this endocrine axis. In the present study we investigated muscarinic and nicotinic cholinergic influences on HPA axis activity in male and female rats by pretreatment with selective cholinergic receptor antagonists followed by stimulation with physostigmine (PHYSO), an acetylcholinesterase inhibitor. Hormonal measures were plasma arginine vasopressin (AVP), adrenocorticotropic hormone (ACTH), and corticosterone (CORT). Male rats had significantly greater AVP and ACTH responses to PHYSO alone than did females. Scopolamine (SCOP) enhanced the AVP response to PHYSO to a greater extent in males than in females. In contrast, mecamylamine (MEC) enhanced the AVP response in females but decreased it in males. SCOP potentiated, and MEC inhibited, the stimulatory effect of PHYSO on ACTH in both sexes, but SCOP potentiation was greater in males, and MEC inhibition was greater in females. Absolute CORT increases following PHYSO were greater in females, but percent increases over baseline were greater in males. Similar to their effects on ACTH responses, MEC attenuated, and SCOP enhanced, CORT responses to PHYSO. These results suggest that cholinergic receptor subtypes may influence HPA axis activity differentially in male and female rats.

Hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: sex differences between major depressives and matched control subjects.

Of heuristic value in understanding the neurochemistry of major depression is whether the hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity that occurs in this illness can be related to putative neurotransmitter dysfunction(s). Cholinergic neurotransmission stimulates hypothalamic corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) secretion, both of which stimulate pituitary corticotropin (ACTH) secretion, but whether the HPA axis in humans is activated only by doses of cholinergic agonists that produce noxious side effects remains controversial. To test the hypothesis of increased cholinergic sensitivity in major depression, physostigmine (PHYSO), a reversible cholinesterase inhibitor, was administered to patients and control subjects at a dose that elevated plasma ACTH, cortisol, and AVP concentrations but produced few or no side effects. Exogenous AVP also was administered to determine if it would augment the effect of low-dose PHYSO on the HPA axis. Twelve premenopausal or estrogen-replaced female major depressives, 12 individually matched female control subjects, eight male major depressives, and eight matched male control subjects underwent four test sessions 5-7 days apart: PHYSO (8 microg/kg IV), AVP (0.08 U/kg IM), PHYSO + AVP, and saline control. Serial blood samples were taken before and after pharmacologic challenge and analyzed for ACTH1-39, cortisol, and AVP. Estradiol and testosterone were also measured at each test session. PHYSO (8 microg/kg) significantly increased plasma ACTH, cortisol, and AVP, while producing no side effects in approximately half the subjects and predominantly mild side effects in the other half. These hormone increases following PHYSO occurred primarily in the female depressives and the male control subjects and were not significantly related to the presence or absence of side effects. The greater the ACTH and AVP responses to PHYSO, the stronger their correlation, suggesting that AVP may have been acting as a secretagogue for ACTH. Administered AVP significantly increased the secretion of ACTH in the patients and control subjects to a similar degree, and AVP given after PHYSO did not augment the HPA axis response to a greater degree in the depressives than in the control subjects. Plasma estradiol and testosterone were within the normal range for all four groups of subjects and were not significantly related to their HPA axis hormone responses. The study results support the hypothesis of heightened cholinergic sensitivity in premenopausal female, but not in male, patients with major depression. The low dose of PHYSO used may represent a useful paradigm for central cholinergic stimulation of the HPA axis.

Plasma neopterin in major depression: relationship to basal and stimulated pituitary-adrenal cortical axis function.

We measured plasma neopterin at baseline and after oCRH and ACTH(1-24) stimulation tests in 35 unmedicated, adult major-depressive patients (mean age = 41 +/- 12 years) and in 35 normal control subjects individually matched to the patients. Neopterin is released by gamma-interferon-stimulated macrophages; because gamma-interferon is secreted by activated T-lymphocytes, elevated circulating neopterin is considered to reflect activation of the cell-mediated immune system. Plasma ACTH(1-39) and cortisol also were measured as indicators of pituitary-adrenal axis activity. Baseline plasma neopterin did not differ significantly between patients and controls (medians = 6.25 and 6.57 microg/l, respectively), but the baseline neopterin:creatinine ratio showed a trend toward lower values in the patients (P < 0.07). There was no apparent plasma neopterin change from baseline (area under the curve-AUC) following oCRH or ACTH(1-24) administration in either group of subjects. As with baseline neopterin, there was no significant patient-control difference in neopterin AUC following either hormone challenge, but there were trends toward lower neopterin:creatinine ratios in the patients following both challenges. In the patients, neither baseline neopterin nor neopterin AUCs following hormone challenge were significantly correlated with age, duration of depressive episode, lifetime number of episodes, melancholic subtype, Hamilton Depression Scale total score, Hamilton factor scores, or the Hamilton suicidality item score.

Pituitary-adrenal cortical axis measures as predictors of sustained remission in major depression.

To determine the relationship of pretreatment hypothalamic-pituitary-adrenal cortical (HPA) axis measures in major depressives to the occurrence of relapse following discontinuation of successful treatment, we compared pretreatment demographic, clinical, and HPA axis measures in 35 patients with DSM-III-R primary major depression divided into two groups. One group (n = 26) required continuing treatment to hold their symptoms in abeyance, and the other group (n = 9) had been successfully tapered off medication, remained in remission, and had been medication-free for at least 1 month. The major features that differentiated the 26 patients who required continuing medication to abate their symptoms from the 9 patients who were successfully discontinued from treatment were trends toward a longer duration of episode prior to initial study and increased baseline corticotropin (ACTH) 1-39, and significantly higher baseline cortisol and cortisol response to ACTH 1-24, in the former group. These results suggest that measures of HPA axis hyperactivity, along with longer duration of the index depressive episode, may predict the need for continuing medication for patients to remain in remission.

Psychobiology and psychopharmacotherapy of unipolar major depression: a review.

Psychopharmacology has continually informed the biological perspective of major depression. Antidepressants affect a variety of neurotransmitters by a wide range of pharmacological actions. The complexity of these neurotransmitter receptor interactions likely underlies the discrepancies observed in biochemical and physiological responses among apparently clinically homogenous depressive subgroups. This report provides an integrated review of the neuroendocrine and neurochemical perspectives of unipolar depression and how these advances influence the psychopharmacotherapy of unipolar major depression.

Neuroendocrine aspects of primary endogenous depression--XIV. Gonadotropin secretion in female patients and their matched controls.

To determine the extent of dysregulation of gonadotropin secretion in depressed women, we measured nocturnal and diurnal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations and the responses of these hormones to gonadotropin releasing hormone (LHRH) in 20 Research Diagnostic Criteria primary, definite endogenous female depressives and in 20 individually matched female normal controls. Fourteen patients and 14 controls were premenopausal, and six patients and six controls were peri/postmenopausal or panhysterectomized. None of the latter was receiving estrogen replacement therapy. The premenopausal patients showed no significant differences in basal nocturnal or diurnal gonadotropin concentrations and no significant differences in hormone concentrations post-LHRH compared to their premenopausal matched controls. In contrast, in the postmenopausal subjects there were (1) significantly increased diurnal vs. nocturnal serum FSH concentrations in the depressives; (2) marginally increased nocturnal, diurnal, and LHRH-stimulated LH concentrations and highly significantly increased LHRH-stimulated FSH concentrations in the depressives compared to their controls; and (3) positive correlations between the LH measures and ratings of depression severity in the patients. These results suggest a dysregulation of the HPG axis in peri/postmenopausal and panhysterectomized female endogenous depressives.

Repair of O6-methylguanine and O4-methylthymidine in F344 rat liver following treatment with 1,2-dimethylhydrazine and O6-benzylguanine.

Concentrations of O6-methylguanine, O4-methylthymidine, and N-7-methylguanine were measured in the livers of Fischer 344 rats following treatment with 1,2-dimethylhydrazine (20 mg/kg, s.c.) alone or in combination with the O6-alkylguanine transferase inhibitor O6-benzylguanine (100 mg/kg, i.p., daily). Animals were sacrificed at 12, 24, 36, or 48 h following 1,2-dimethylhydrazine exposure. Direct measurement of alkyltransferase demonstrated that daily treatment with O6-benzylguanine completely eliminated detectable alkyltransferase activity in the livers of treated rats. Adducts in liver DNA were quantitated by high performance liquid chromatography separation followed by fluorescence detection, UV absorbance, and/or specific radioimmunological assays. In animals exposed to 1,2-dimethylhydrazine alone O6-methylguanine concentrations declined rapidly, whereas animals exposed to both O6-benzylguanine and 1,2-dimethylhydrazine showed less removal of O6-methylguanine, with significant differences between the two populations appearing at 36 and 48 h. O4-Methylthymidine removal also differed significantly between the two groups, with O6-benzylguanine-treated animals exhibiting higher concentrations of adducts at 36 and 48 h. O6-Benzylguanine treatment had no effect on the removal of N-7-methylguanine. These results show that the rate of disappearance of both O6-methylguanine and O4-methylthymidine is slower following alkyltransferase depletion, suggesting that mammalian alkyltransferase is involved in the removal of O4-methylthymidine lesions as well as O6-methylguanine lesions.