M. V. Gianelli

Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy

Impaired reproductive function is thought to frequently affect women with epilepsy, mainly when seizures originate in the temporal lobe. In this study, we evaluated menstrual cycle features and assessed ovulation by determining luteal progesterone (Pg) levels in 101 consecutive women with epilepsy (36 with idiopathic generalized epilepsy -IGE; 65 with partial epilepsy -PE), aged between 16 and 50 years, treated with various antiepileptic drugs (AED). PE originated in the temporal lobe (TLE) in 40 subjects, in the frontal lobe in 13, in the parietal lobe in 2, while the origin of focal seizures remained undetermined in 10 patients. In all patients, menstrual and reproductive history, body mass index, hair distribution and hormonal pattern were assessed. Suprapubic ovary ultrasound (US) examination was carried out in 83 patients (28 with IGE, 55 with PE). Three patients with IGE and one with PE were amenorrheic. Oligomenorrhea occurred in 16 patients, polymenorrhea in 2. Changes in menstrual cyclicity were independent from epilepsy type (19.4% in IGE; 23.1% in PE) and from origin of focal discharges (22.5% of patients with TLE; 20.0% with origin in other brain areas). Luteal Pg levels remained below 2 ng/ml in 30 patients independently of epilepsy type. Corpus luteum dysfunction was combined with hyperandrogenism in 15 of these patients. In the other cases different alterations of hypothalamus-pituitary-ovary axis were observed. Valproic acid blunted luteal Pg surge more frequently than other AED. Polycystic ovaries (PCO) were observed in 14 (16.9%) patients (21.0% with IGE; 14.5% with PE). These prevalences are not higher than those reported in the general population. Among PE patients, PCO was found in 1 case with undertemined focal origin and in 7 TLE cases, who also had ovary volume significantly larger than patients with seizures originating from the frontal or parietal lobe. Epileptic women exhibited an increased occurrence of multifollicular ovaries (MFO) found in 12 cases (14.4% vs 5% in the general population). However, no defined hormonal or clinical pictures were associated with this US alteration in most patients. These findings reappraise the impact of ovary alterations in women mainly affected by mild to moderate epilepsy, on differing AED regimens, with the exception of more frequent ovulatory dysfunction and PCO occurrence in patients taking VPA.

Relationship between Cognitive Function, Growth Hormone and Insulin-Like Growth Factor I Plasma Levels in Aged Subjects

Basal growth hormone (GH) and insulin-like growth factor I (IGF-I) as well as GH responses to GH-releasing hormone (GHRH) were studied in 22 subjects (7 females, 15 males), aged between 65 and 86 years. The study was aimed at investigating the possible correlations between the age-dependent GH-IGF-I axis decline and the cognitive function – assessed by the Mini Mental State Examination (MMSE). The relationship between hormonal data, cognition and age, body weight, body mass index (BMI), some nutritional indices (triceps skinfolds, TSF, mid-arm circumference, MAC), and physical activity – quantified by the physical functioning index (PFI) – were also analyzed. GH basal levels were within the normal range, while GH responses to GHRH were blunted in most cases. GH peaks after GHRH were directly correlated with GH basal values. IGF-I serum levels were found to be in the lower part of the reference range for adult subjects or below it. GH responses to GHRH, but not GH and IGF-I basal levels, were inversely correlated with subject age. GH secretion areas after GHRH were inversely correlated with BMI, but no further correlations between GH data and clinical or nutritional parameters were found. MMSE values directly correlated with MAC and PFI values. IGF-I levels were directly correlated with MMSE scores, being lowered in patients with more advanced cognitive deterioration, and with MAC values – the decrease of which is thought to reflect protein caloric malnutrition – but not with body weight, BMI, TSF and PFI. MMSE-related protein caloric malnutrition and decreased physical activity possibly take part in affecting IGF- I function in subjects with mild cognitive impairment and, reciprocally, IGF-I decrement might affect neuronal function.

Quantitative Electroencephalography and Regional Cerebral Blood Flow: Discriminant Analysis between Alzheimer’s Patients and Healthy Controls

Forty-two patients with probable Alzheimer’s disease (AD) and 18 elderly healthy controls underwent quantitative EEG (qEEG) and regional cerebral blood flow (rCBF; 133Xe clearance) examinations. Correlations were sought between relative qEEG band powers and percent rCBF values in a posterior temporoparietal region of interest in either hemisphere. Moreover, stepwise discriminant analysis was applied to study the accuracy of the two techniques in differentiating AD from healthy ageing. rCBF and qEEG were correlated with one another, especially in the right hemisphere (p values ranging from <0.001 to <0.01). Significant correlations were found between Mini Mental State Examination (MMSE) and relative power of both the 2- to 6-Hz and the 6.5- to 12-Hz bands on either side (p < 0.001), and between MMSE and left rCBF (p < 0.005), while the correlation with right rCBF was poorer (p < 0.02). The statistical procedure identified the right values of both examinations for the discriminant analysis. Sensitivity of qEEG and rCBF employed together was 88% and specificity 89%, with a total accuracy of 88.3%. The unrecognized patients (n = 5) were affected by mild AD (4 scoring 3 at the Global Deterioration Scale and 1 scoring 4). qEEG alone showed an accuracy of 77% in the whole group and of 69% in mild AD, and rCBF alone an accuracy of 75% in the whole group and of 71% in mild AD. It is concluded that qEEG and rCBF examinations employed together are accurate tools to differentiate AD from normal ageing, although a lower degree of accuracy is achieved in mildly demented patients.

Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia

ABSTRACT. Changes in the hypothalamus-pituitary- adrenal axis (HPAA) function, entailing elevated cortisol circulating titres, occur in aging and in some neurological conditions, such as Alzheimer’s disease (AD). Excess cortisol has neurotoxic effects which affect hippocampal neurones. Dehydroepiandrosterone sulphate (DHEAS) has an antiglucocorticoid activity and neuroprotective effects, but its levels decrease with aging. Glucocorticoids influence the production of insulin-like growth factor-I (IGF-I) and modify its systemic and neurotrophic biological activity by inducing changes in IGF-binding proteins (IGFBPs). We looked for relationships between cortisol, DHEAS levels, and IGF-I - IGFBPs system in AD. Cortisol, DHEAS and GH levels at 02:00, 08:00, 14:00, 20:00 h, basal IGF-I, IGFBP-1 and IGFBP-3 levels were determined by RIAs or IRMA in 25 AD patients, aged 58-89 yr, and in 12 age-matched healthy controls. AD subjects had higher cortisol, lower DHEAS levels and increased cortisol/DHEAS ratio (C/Dr) than controls. In AD cases, total IGF-I, IGFBP-3, and IGF-I/IGFBP ratios were significantly lowered, while IGFBP-1 levels were significantly higher than in controls. We found a significant inverse correlation between IGF-I and IGFBP-3 levels vs C/Dr, and between both IGF-I/IGFBPs ratios vs mean cortisol levels. IGFBP-3 correlated directly with DHEAS. Cortisol was directly and IGF-I inversely correlated with cognitive impairment. In AD patients we found that alterations in HPAA function and elevated C/Dr are related to lowered total and free IGF-I levels. These findings and their relationship to cognitive impairment suggest that changes in hormonal set-up might influence the clinical presentation of the disease.

Hippocampal Perfusion and Pituitary-Adrenal Axis in Alzheimer’s Disease

The hippocampus is involved in Alzheimer’s disease (AD) and regulates the hypothalamus-pituitary-adrenal axis (HPAA). Enhanced cortisol secretion has been reported in AD. Increased cortisol levels affect hippocampal neuron survival and potentiate β-amyloid toxicity. Conversely, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are believed to antagonize noxious glucocorticoid effects and exert a neuroprotective activity. The present study was aimed at investigating possible correlations between hippocampus perfusion – evaluated by SPECT – and HPAA function in AD. Fourteen patients with AD and 12 healthy age-matched controls were studied by 99mTc-HMPAO high-resolution brain SPECT. Plasma adrenocorticotropin, cortisol, and DHEAS levels were determined at 2.00, 8.00, 14.00, 20.00 h in all subjects and their mean values were computed. Cortisol/DHEAS ratios (C/Dr) were also calculated. Bilateral impairment of SPECT hippocampal perfusion was observed in AD patients as compared to controls. Mean cortisol levels were significantly increased and DHEAS titers were lowered in patients with AD, as compared with controls. C/Dr was also significantly higher in patients. Using a stepwise procedure for dependent SPECT variables, the variance of hippocampal perfusional data was accounted for by mean basal DHEAS levels. Moreover, hippocampal SPECT data correlated directly with mean DHEAS levels, and inversely with C/Dr. These data show a relationship between hippocampal perfusion and HPAA function in AD. Decreased DHEAS, rather than enhanced cortisol levels, appears to be correlated with changes of hippocampal perfusion in dementia.

Dementia: A neuroendocrine perspective

The etiology of Alzheimer’s disease (AD) has not been as yet completely defined. Genetic, environmental and neurophysiological aspects should all be taken into account. The disease has also neuroendocrine implications, some of which are discussed in this review. It is known that stress and glucocorticoids may affect neurone survival. On the contrary, some data indicate that DHEA and DHEAS exert a neuroprotective action. In AD, changes in hypothalamic-pituitary-adrenal axis function have been reported. Experimental and clinical evidence indicates that glucocorticoid hypersecretion and DHEAS levels decrement may add to hippocampal dysfunction in aging and in AD. Glucocorticoid and Σ-amyloid concur in the mechanism of neurone damage, as well as excitatory amino acids (EAA), Ca++ and reactive oxygen species (ROS). The neuroprotective effects exerted by IGFs are also hindered in aging and even more in AD. Production and biological actions of IGFs are negatively influenced by cortisol hypersecre-tion and DHEAS decrease in patients with AD.

Dexamethasone effects on cortisol secretion in Alzheimer’s disease: Some clinical and hormonal features in suppressor and nonsuppressor patients

Alterations in the hypothalamic-pituitary-adrenal axis (HPAA) and failure of dexamethasone (DXT) to suppress cortisol secretion occur in Alzheimer’s disease (AD). This study was aimed to settle possible differences in some clinical (age, body weight, body mass index, dementia severity) and hormonal parameters in AD patients non-responders to overnight 1 mg-DXT suppression test compared with the responder subjects. ACTH, cortisol and dehydroepiandrosterone sulphate (DHEAS) day-time levels were assessed in 25 AD patients and in 12 age-matched healthy controls before DXT administration. In view of their neuroprotective effects, plasma levels of Insulin-like Growth Factor-I (IGF-I) and of IGF-Binding Proteins (IGFBPs) were also determined. After DXT, 8 AD subjects (32%) showed cortisol levels above the conventional cut-off of 140 nmol/L. No significant differences were found in clinical parameters in suppressor vs nonsuppressor patients. AD subjects showed higher cortisol, cortisol/DHEAS ratios, and lower DHEAS levels in comparison with controls. Both ACTH and cortisol levels were not different in suppressor and nonsuppressor patients, but DHEAS levels were significantly lower in nonsuppressor cases, who also exhibited ACTH and cortisol periodicities more altered than in suppressor and in control subjects. IGF-I and IGFBP-3 levels were lower and those of IGFBP-1 higher in nonsuppressor than in suppressor cases and in healthy controls. IGF-I/IGFBPs system data were correlated with cognitive impairment and adrenal steroid levels in AD patients.

GROWTH HORMONE SECRETION IN PRIMARY DEGENERATIVE DEMENTIA: CORRELATIONS WITH COGNITIVE IMPAIRMENT

Changes in brain peptides and neurotransmitters are thought to elicit alterations of growth hormone (GH) secretion in dementia. Baseline GH levels and hormone responses to GH‐releasing hormone (GHRH)—administered alone or after pyridostigmine pretreatment—were evaluated in 17 patients, aged 52–83, with primary degenerative dementia quantified by the Clinical Dementia Rating (CDR) Scale and the Mini‐Mental State Examination (MMSE) with a view to detecting correlations between neuroendocrine and clinical data. Basal GH levels were not statistically different in patients and in age‐matched controls. However, when patients were split into the three CDR groups of disease severity, basal GH levels were significantly higher in those with more severe dementia than in all other patients and in controls. GH responses to GHRH, evaluated both in terms of peaks attained after simulation and of secretion areas under the curve (AUC), were significantly higher in patients than in controls after pyridostigmine pretreatment, but not after the infusion of GHRH alone. Patients with mild to moderate dementia had GH peaks after GHRH higher than more severe patients. Pyridostigmine did not potentiate GHRH effects in the more severe cases. The scores on Reys 15‐word test for memory function were directly correlated with GH peaks after GHRH. No correlations were found between GH data, age, body weight, disease duration and scores at other psychometric assessments such as MMSE, Ravens matrices, verbal fluency or WAIS tests.