Angelo Cagnacci

Neuroendocrine and clinical effects of transdermal 17β-estradiol in postmenopausal women

The neuroendocrine and clinical effects of transdermal 17 beta-estradiol (rated at 50 micrograms/day; TTS 50) were studied in 40 postmenopausal women; ten additional postmenopausal women did not receive any drugs. The changes in LH and rectal temperature induced by the infusion of the opioid antagonist naloxone (10 mg i.v. bolus plus 10 mg/h for 4 h) were used to evaluate the central activity of endogenous opioid peptides. TTS 50 increased opioid activity, as evidenced by the restoration of the LH response (P less than 0.01) and the enhancement of the hypothermic effect (P less than 0.05) of naloxone. A greater reduction in hot flushes was observed in TTS 50-treated subjects than in untreated women, with the maximal effect of TTS 50 achieved after 3 months of therapy. TTS 50 did not modify the concentrations of circulating lipids, glucose or liver enzymes but reduced the biochemical parameters indicative of bone reabsorption. Bone density of the distal radius significantly increased during TTS 50 (P less than 0.02), reaching its maximum value after 6 months of therapy. Thereafter bone density declined, but more slowly than in untreated women. Our data suggest that TTS 50 has marked neuroendocrine effects, that it diminishes the incidence of hot flushes and reduces bone demineralization. By contrast, it has a very little, if any, metabolic impact on the liver or on glucose and lipid metabolism.

Chronic bromocriptine administration restores luteinizing hormone response to naloxone in postmenopausal women

To evaluate whether dopaminergic treatment may modify endogenous opioid activity at the hypothalamic-pituitary level, the effects of naloxone infusion (1.6 mg/h for 4 h) on luteinizing hormone (LH) se

Effects of different dopamine agonists and antagonists on post-menopausal hot flushes

The dopaminergic system seems to be involved in both pulsatile luteinizing hormone (LH) secretion and hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectiveness of dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessed scores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one of the following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergic agent, Liposom; the antidopaminergic drug, veralipride or the peripheral antidopaminergic agent, domperidone. All of these treatment regimens were effective in alleviating hot flushes, but the pharmacological agents proved to be more effective than the placebo. A direct dopaminergic action is hypothesized in the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through different indirect mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on tuberoinfundibular dopamine (TIDA) neurons with a secondary dopamine-like activity, or stimulation of the opioid system.

INFLUENCE OF OESTRADIOL AND PROGESTERONE ON PULSATILE LH SECRETION IN POSTMENOPAUSAL WOMEN

Pulsatile LH secretion was studied in six healthy postmenopausal women. Blood samples were obtained every 10 min during an 8‐h saline infusion performed before and during the administration of transdermal oestradiol alone (E2; 50 μg/day) and in combination with vaginal progesterone (P; 100 mg twice daily). Plasma E2 and P levels reached values similar to those found in the early follicular phase and in the luteal phase of the menstrual cycle, respectively. The mean plasma LH levels significantly decreased (P < 0.01) during trans‐dermal E2 with and without vaginal P. A significant increase in the frequency (P < 0.025) and the amplitude (P <0.05) of LH pulses was observed during transdermal E2. The administration of vaginal P to oestrongenized women significantly blunted the frequency (P < 0.05) and enhanced the amplitude (P<0.05) of LH pulses. In all experimental conditions, the mean plasma LH levels showed a positive linear correlation with the amplitude of LH pulses. The present results show that peripheral levels of E2, similar to those of the early follicular phase of the menstrual cycle, can influence the pulsatile pattern of LH secretion, enhancing the frequency and the amplitude of LH pulses. In oestrogenized patients, the increase of peripheral P plasma levels to postovulatory values restored a pulsatile pattern of LH secretion similar to that of the early luteal phase of menstrual cycle.

Interaction between veralipride and the endogenous opioid system in the regulation of body temperature in postmenopausal women

Abstract The influence of endogenous opioid peptides on body thermoregulation has been studied in untreated postmenopausal women and in the same subjects after chronic administration of the antidopaminergic drug veralipride (200 mg/day for 20 days). Subjects randomly received an infusion of the opioid antagonist naloxone (1.6 mg/h for 4 h) or saline on two consecutive days, both before and after ceralipride treatment. In untreated subjects body core temperature, as evaluated by rectal temperature, did not vary during saline infusion, whereas a significant decrease was observed during naloxone infusion. Chronic administration of veralipride significantly increased thenhypothermic response to naloxone. Therefore, veralipride seems to increase the activity of endogenous opioid peptides on mechanisms which regulate body temperature in postmenopausal women.

Regulation of body temperature in postmenopausal women: interactions between bromocriptine and the endogenous opioid system

The role exerted by the endogenous opioid system on thermoregulation has been studied in nine postmenopausal women before and after the chronic administration of the dopamine agonist bromocriptine (5 mg/day). These women randomly received an infusion of the opioid antagonist naloxone (1.6 mg/h for 4 h) or saline on two consecutive days, before and after 30 days of bromocriptine administration. Body temperature as evaluated by rectal temperature, did not vary during saline infusion performed both before and after 30 days of bromocriptine administration. In untreated women naloxone infusion significantly reduced body core temperature. The hypothermic response to naloxone was significantly greater following chronic bromocriptine administration. These results indicate that bromocriptine seems to increase the activity of the endogenous opioid system on the mechanisms which regulate body temperature in postmenopausal women.

Effect of naloxone on body temperature in postmenopausal women with Parkinson's disease

The role exerted by the endogenous opioid system on thermoregulation has been studied in six postmenopausal women affected by Parkinsons disease and in 6 age-matched, normal postmenopausal women, as controls. The women randomly received an infusion of the opioid antagonist naloxone (1.6 mg/h for 4 h) or of saline on two consecutive days. Body temperature, as evaluated by rectal temperature, was significantly lower (p less than 0.05) in Parkinsonian than in normal women, and it did not vary during saline infusion, in either groups. Naloxone infusion significantly reduced (p less than 0.01) body temperature in normal postmenopausal women, but it was unable to modify body temperature in women affected by Parkinsons disease. The low basal body temperature values and the inability of naloxone to exert a hypothermic effect in women suffering from Parkinsons disease seem to constitute further evidence for an impaired regulation of body temperature and impaired activity of the endogenous opioid system in this pathology.

Reduced luteinizing hormone secretion in women with Parkinson's disease.

SummaryPlasma luteinizing hormone (LH) levels were significantly lower in 10 postmenopausal women with Parkinsons disease (PD) compared to agematched controls. The remaining hypophyseal hormones and gonadal steroids were similar in PD patients and in controls, suggesting a selective alteration of hypothalamic dopaminergic mechanisms which regulate LH secretion.

Sex steroids modulate prolactin response to naloxone in postmenopausal women.

To evaluate whether ovarian steroids modify the prolactin (PRL) response to opioid receptor blockade, the effects of naloxone infusion (1.6 mg/h for 4 h) on PRL secretion were studied in 5 postmenopausal women. Naloxone infusion was performed in basal conditions and after chronic oral treatment with conjugated estrogens (CE) (1.25 mg/day, for 20 days) or CE plus medroxyprogesterone acetate (MPA) (10 mg/day, for 20 days). Under basal conditions, 17 beta-estradiol, estrone, gonadotropin, and PRL plasma levels were in the normal range for postmenopausal women, and naloxone failed to affect PRL secretion. Naloxone induced a significant PRL increase after CE treatment alone (p less than 0.001) or in combination with MPA (p less than 0.001). The increase was significantly higher (p less than 0.05) after CE + MPA treatment than after CE treatment alone. These data suggest that steroids modulate the stimulatory effect of naloxone on PRL secretion in postmenopausal women.

Effects of the antidopaminergic drug veralipride on LH and PRL secretion in postmenopausal women

Patterns of LH and PRL secretion have been evaluated in 15 postmenopausal women before and after the chronic blockage of the D2 dopamine receptors with veralipride (100 mg twice daily, for 30 days). In addition, the possible influence of the antidopaminergic drug on the activity of the endogenous opioid system has been evaluated by the infusion of the opioid antagonist naloxone, performed before and during veralipride administration. Mean plasma LH levels were significantly blunted (p < 0.05) and mean plasma PRL levels were significantly increased (p < 0.001) by veralipride administration. The frequency of both LH and PRL secretory pulses was not modified, while the mean pulse amplitude of both hormones was significantly increased (p < 0.05 for LH; p < 0.001 for PRL) by veralipride administration. In untreated postmenopausal women naloxone infusion did not modify LH secretion. Following veralipride, the infusion of naloxone significantly increased (p < 0.05) the mean plasma LH levels, had no influence on the frequency and significantly reduced (p < 0.01 ) the amplitude of LH pulses, expressed as the percent increase from the nadir to the peak. Both before and after veralipride administration, naloxone failed to modify the pattern of PRL secretion. In untreated postmenopausal women, the percentage of concomitant PRL and LH pulses was significantly higher (p < 0.001) during naloxone than during saline infusion, and this effect was amplified by veralipride administration (p < 0.01). The present data suggest that in postmenopausal women, the chronic blockage of the D2 dopamine receptors with veralipride significantly reduces the mean plasma LH levels and significantly increases the amplitude of LH pulses, presumably through the activation of the endogenous opioid system.