Felice Petraglia

Dementia of the Alzheimer type and hypothalamus-pituitary-adrenocortical axis: changes in cerebrospinal fluid corticotropin releasing factor and plasma cortisol levels

The activity of the hypothalamus‐pituitary‐adrenocortical (HPA) axis was explored in 10 patients with dementia of the Alzheimer type (DAT) and in 11 age‐matched controls, by measuring 1) corticotropin‐releasing factor (CRF) levels in cerebrospinal fluid (CSF), 2) the circadian changes of plasma cortisol, 3) and 4) the plasma cortisol response to dexamethasone suppression test (DST) and to CRF stimulation test. CSF CRF levels in DAT were significantly higher than in controls and inversely related to the Mini Mental State (MMS) score. The patients also displayed increased morning (0800 h) plasma cortisol values, with higher mesor and amplitude in the circadian pattern. Dexamethasone resistance was shown by 6 of the 10 DAT subjects. Plasma cortisol response to CRF administration was similar in the two groups, except for the peak values, which in DAT patients were reached earlier than in controls. The present data suggest an overactivity of HPA axis in DAT; its possible role in the evolution of the disease is discussed.

Premenstrual fall of plasma β-endorphin in patients with premenstrual syndrome *

Plasma β -endorphin ( β -EP), β -lipotropin ( β -LPH), and Cortisol concentrations were measured by perimenstrual period in 11 patients affected by premenstrual syndrome (PMS) and in 8 asymptomatic healthy volunteers. Blood samples were collected every 2 to 3days, for 1month, starting from midcycle. The Menstrual Distress Questionnaire (MDQ) was administered during the testing period. Plasma β -LPH and Cortisol levels remain stable during the perimenstrual period, in both controls and PMS patients. On the contrary, PMS patients showed a decrease of plasma β -EP in the week preceding menses and during the first days of menstrual flow. β -EP values of PMS patients regain normal levels during the next follicular phase. No changes of β -EP levels were recorded in asymptomatic women. MDQ scores revealed that PMS patients complained of water retention, pain discomfort, and mood swings. The transient and reversible decrease of plasma β -EP in PMS patients near to and at menses remains to be clarified.

Hypothalamic amenorrhea: evidence for a central derangement of hypothalamic-pituitary-adrenal cortex axis activity*

OBJECTIVE To evaluate the activity of the hypothalamic-pituitary-adrenal axis (HPA) in patients with hypothalamic amenorrhea. PATIENTS, PARTICIPANTS Amenorrheic women with a history of emotional stressful events and eumenorrheic women as control group were studied. DESIGN Pulsatile cortisol (F) secretion over a 4-hour period of time and plasma F responses to various neuroendocrine tests (naloxone, fenfluramine, corticotropin-releasing hormone [CRH], adrenocorticotropic hormone) were investigated. RESULTS Women with hypothalamic amenorrhea showed a F secretory pattern higher than normal women. In addition, the lack of naloxone or fenfluramine-induced release of F and a blunted F response to CRH test were observed. CONCLUSION The increased activity of HPA in patients with hypothalamic amenorrhea is associated with an impaired activity of some central pathways (opioids and serotonin), suggesting multiple alterations in the hypothalamic control of pituitary-adrenal axis in amenorrheic women.

Effects of etoperidone on sympathetic and pituitary-adrenal responses to diverse stressors in humans.

The effects of the psychotropic drug etoperidone on the response to laboratory stressors was investigated in a controlled study. Cardiovascular and hormonal (catecholamines, corticotropin, and cortisol) measurements were made in a group of young, healthy volunteers during a cold pressor test (CPT), a mental arithmetic test (MAT), and insulin-induced hypoglycaemia (ITT). One-week treatment with etoperidone (ETO) (150 mg/day, orally) reduced basal and stress-induced values of systolic and diastolic blood pressure (BP) on CPT, while it did not alter catecholamine output in response to the stressor. Cardiovascular response was also attenuated after ETO on MAT, in the absence of any hormone changes. Adrenocorticotropic hormone (ACTH) and cortisol secretions were markedly reduced on ITT after ETO, whereas catecholamine outflow and cardiovascular parameters were substantially unaffected. These findings on ITT suggest that the anti-serotoninergic and anti-alpha 1-adrenergic activities of ETO may be used in the pharmacological control of the potentially detrimental consequences of the stress response.

Circulating Opioids and Plasma Renin Activity in Insulin-Dependent Diabetics with Renal Haemodynamic Alterations

Circulating opioids were studied in insulin-dependent diabetics with renal haemodynamic alterations. Higher circulating beta-endorphin (beta-EP) and lower beta-lipotropin (beta-LPH) levels were found in patients with glomerular hyperfiltration than in diabetics with normal glomerular filtration rate (GFR) and controls. Moreover, significantly positive correlations between beta-EP and GFR, and between beta-EP and renal plasma flow were demonstrated in these patients. On the contrary, reduced beta-EP levels were observed in diabetics with impaired GFR and overt nephropathy. Plasma renin activity was increased in diabetics with glomerular hyperfiltration and reduced in diabetics with overt nephropathy. Circulating opioids might, therefore, play a role in renal haemodynamic alterations, both in patients with early and advanced glomerular changes.

N‐terminal ACTH fragments increase the CSF β‐EP content in Alzheimer type dementia

ABSTRACT‐ Eleven patients with presenile Alzheimer type dementia (ATD) were treated with N‐terminal ACTH fragments for 14 days. No change in cognitive functions was observed during the treatment. A significant increase in CSF β‐endorphin (β‐EP) levels was found, while ACTH and β‐lipoprotein remain unaffected. The possibility that ACTH and its moieties could interfere with β‐EP activities in CNS is discussed.

Endocrinology of Delivery

Parturition is a coordinated process of transition from a quiescent myometrium to an active rhythmically contractile state, requiring complex interplay between placental, fetal, and maternal compartments. It involves the synchronization of myometrial activity and structural changes of the cervix, leading to regular coordinated uterine contractions, cervical effacement and dilatation and rupture of membranes. Multiple endocrine, paracrine and autocrine events and overlapping maternal/fetal control mechanisms trigger parturition. In fact, hormonal, neuroendocrine, inflammatory, and immune mechanisms are involve in the activation of labor. Placenta endocrine function contributes to labor onset and progression. Progesterone withdrawal, increased estrogen bioavailability, corticotrophin releasing hormone (CRH) and neuroendocrine mediators rise, increased prostaglandins, and oxytocin are key events in parturition.

Risk Factors for Gestational Diseases

Preterm delivery (PTD) and pre-eclampsia (PE) are severe pathologies that may affect and compromise the course of pregnancy, and adverse pregnancy outcomes are important causes of perinatal morbidity and mortality [1].

Hormonal Replacement Therapy, Cognitive Disturbances, and Alzheimer’s Disease

Sex steroid hormones modulate the synthesis and release of neurotransmitters and neuropeptides through the binding with specific receptors in the central nervous system (CNS). In the last ten years, several epidemiological and clinical studies have shown an impairment of psychological and cognitive functions in postmenopausal women. The withdrawal of ovarian steroid production and neuroendocrine modifications have been directly related to an alteration of the cognitive function. Clinical studies have shown that hormone replacement therapy (HRT), especially that of estrogen, plays an important role in enhancing and maintaining short-term memory and abstract reasoning in postmenopausal women, whereas the performance of nontreated postmenopausal women decreases. The most severe decline of cognitive functions occur in Alzheimer’s disease (AD) patients. The incidence of AD is higher in women than in age-matched men and the cognitive function impairment is more pronounced in women than in men. An impairment of the cholinergic neuroendocrine system is involved in the pathogenesis of cognitive disturbances and of AD due to a reduction of choline acetyltransferase activity. Cholinergic pathway modifications occur in postmenopausal women with the cessation of ovarian activity. Experimental and clinical trials suggest that estrogen reverses the decrease of choline acetyltransferase in postmenopausal women, enhances cognitive functions, and may prevent the incidence of AD. Recent studies have demonstrated that glial cells and neurons are able to synthesize neuroactive steroids, starting from cholesterol, as well as metabolizing steroid hormones originating in the adrenal gland. Neurosteroids are active in modulating stress adaptive responses and memory.

Changes of Activin A Secretion in Gestational Diseases

Among the various tissues producing inhibin, activin, and follistatin, the gestational intrauterine tissues—placenta, decidua, and fetal membranes-have a major interest. A possible functional involvement of these proteins in reproductive physiology has been suggested. Inhibin and activin act within the human placenta through a cell-to-cell communication (paracrine) or within the same cells (autocrine), locally modulating placental hormonogenesis, cell-mediated immune function, and growth and differentiation of embryo and fetus. In addition, inhibin and activin may also enter the maternal and fetal circulation and have an endocrine effect in the physiology of pregnancy. The changes of activin and inhibin concentration in gestational biological fluids (maternal serum, umbilical cord serum, and amniotic fluid) thus reflect the changes of placental inhibin and activin synthesis and secretion.