The effect of light on core body temperature is mediated by melatonin in women.

Acute exposure to bright light at night reduces the nocturnal decline of core body temperature (cBT) and inhibits melatonin secretion in men. Since inhibition of melatonin secretion by beta-adrenergic blockade reduces the nocturnal decline of cBT by 40% in women, experiments were performed to investigate whether the thermoregulatory effect of light is mediated by modifications of melatonin secretion in cycling women. Results show that the elevation of cBT induced by nocturnal exposure to bright light (3000 lux) can be reversed completely by circumventing the decline of serum melatonin levels with concurrent oral administration of melatonin. Our finding establishes melatonin as the mediator of the effect of light on cBT in women and provides a rationale for the use of orally administered melatonin as an aid in the reentrainment of the cBT rhythm in desynchronized conditions.

Prolonged opioid blockade does not influence luteinizing hormone modifications of the follicular and luteal menstrual phases.

Although an acute opioid withdrawal markedly modifies LH secretion in the different phases of the menstrual cycle, whether a sustained opioid blockade imbalances spontaneous LH modifications associated with the progression of the follicular or luteal menstrual phases is presently unknown. Accordingly, normal cycling women during either the follicular (n = 14) or luteal (n = 14) menstrual phase, randomly and in double blind fashion, received either placebo (n = 7 for each phase) or 50 mg/day of the oral opioid antagonist naltrexone (n = 7 for each phase). In each subject, LH pulsatility (10-min blood drawing for 8 h) and the pituitary LH response to a 10-micrograms GnRH stimulus were investigated at baseline and on the fifth day of placebo/naltrexone administration. In the follicular phase, after placebo treatment, the number and amplitude of LH pulses did not significantly vary, whereas mean LH levels (P < 0.01) and the LH response to GnRH (P < 0.05) were significantly increased. The same occurred after naltrexone treatment, when significant increases in both mean LH levels (P < 0.02) and LH response to GnRH (P < 0.025) were observed. In the luteal phase, after placebo administration, the frequency of LH pulses and mean LH levels were not modified, but both the amplitude of LH pulses (P < 0.025) and the LH response to GnRH were reduced (P < 0.02). The same occurred after naltrexone treatment, when significant decreases in both the amplitude of LH pulses (P < 0.05) and the LH response to GnRH (P < 0.05) were observed. During both phases of the menstrual cycle, the modifications observed during naltrexone treatment were similar and not significantly different from those observed during placebo. The present data do not support important modulatory functions for endogenous opioid peptides on spontaneous LH modifications occurring with the progression of the follicular or the luteal menstrual phases.

Melatonin enhances the luteinizing hormone and follicle-stimulating hormone responses to gonadotropin-releasing hormone in the follicular, but not in the luteal, menstrual phase.

Exogenous melatonin enhances LH pulse amplitude and mean LH levels in women during the follicular, but not the luteal, menstrual phase. In this study we investigated whether an increased pituitary response to GnRH is involved in the stimulatory effect of melatonin. Eight normal cycling women were studied on 2 consecutive days during the follicular stage (days 4-6), and eight were studied during the luteal phase (days 19-21) of the menstrual cycle. On 2 consecutive days, each women received, randomly and in a double blind fashion, placebo or 3 mg melatonin (1 mg at 0800, 1000, and 1200 h), whereas the pituitary LH and FSH responses to GnRH were tested by the iv administration of three submaximal doses of GnRH (1 microgram at 0900 h, 5 micrograms at 1100 h, and 10 micrograms at 1300 h). In the follicular phase, melatonin administration enhanced the LH and FSH responses to all three GnRH stimuli, whereas in the luteal phase, melatonin administration was ineffective. The present data indicate that an enhancing effect of melatonin on the LH and FSH responses to submaximal GnRH stimuli is evident in the follicular, but not the luteal, phase of the menstrual cycle and infer an endocrine window for the effect of melatonin on gonadotropin secretion.

Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women.

The impact of a 3-month continuous administration of transdermal estradiol (E2-TTS 50; 50 micrograms/day) or oral conjugated estrogen (CE; 0.625 mg/day) on glucose and lipid metabolism was investigated in two groups (n = 15/group) of postmenopausal women. Fasting levels of glucose, insulin, and C-peptide; C-peptide/insulin ratio (index of hepatic insulin clearance); and their responses to a 75-g oral glucose tolerance test (OGTT) were evaluated before and after 3 months of continuous estrogen administration. E2-TTS 50 modified carbohydrate metabolism, decreasing fasting insulin levels (P less than 0.01) and increasing the pancreatic islet response to glucose challenges, as indicated by an increased integrated value of the C-peptide curve associated with OGTT (P less than 0.05). Despite greater C-peptide secretion, integrated peripheral insulin after OGTT was decreased (P less than 0.05). The resulting increase in the integrated curve of the molar C-peptide/insulin ratio (P less than 0.01) indicated elevated hepatic insulin clearance after E2-TTS 50 administration. CE treatment did not modify carbohydrate metabolism, except for reducing fasting glucose levels (P less than 0.01). Neither therapy modified lipid metabolism, but a slight increase in circulating triglycerides (P less than 0.01) was observed during CE administration. Our data show that the addition of low doses of natural estrogens does not negatively influence glucose and lipid metabolism in postmenopausal women. By contrast, reversal of postmenopausal hypoestrogenism to early follicular phase estrogenic values with E2-TTS 50 administration seems to exert a beneficial effect on glucose metabolism by increasing hepatic insulin clearance.

Effects of transdermal 17 beta-estradiol treatment and naloxone infusion on gonadotropin response to gonadotropin-releasing hormone in postmenopausal women.

Estrogens exert both inhibitory and stimulatory effects on the secretion of GnRH and gonadotropins in women. The endogenous opioid peptides seem to mediate, at least in part, the inhibitory action exerted by estrogens on LH secretion. However, the mechanisms that mediate the stimulatory effect of estrogens on LH secretion are still unclear. The present study was performed to evaluate whether the endogenous opioid peptides could also participate in the stimulatory effect that estrogens exert on the gonadotropin response to GnRH. In postmenopausal women, a GnRH test was performed both under basal conditions and during the second month of treatment with transdermal 17 beta-estradiol (E2). In untreated postmenopausal women, two different doses of naloxone infusion failed to modify the LH and FSH responses to GnRH stimulation. During treatment with transdermal E2, the LH response to GnRH was significantly increased, while the FSH response was similar to that before treatment. Naloxone completely counteracted the enhanced LH response to GnRH observed during E2 treatment. On the other hand, naloxone did not significantly modify the FSH response to GnRH. The present results confirm that E2 exerts a sensitizing effect on the pituitary LH response to GnRH and suggest that the endogenous opioid system could be involved in this effect.

Insulin, insulin-like growth factor I (IGF-I) and IGF-II enhance basal and gonadotrophin-releasing hormone-stimulated luteinizing hormone release from rat anterior pituitary cells in vitro.

The role of insulin-like growth factor I (IGF-I) and IGF-II on luteinizing hormone (LH) release is still unclear. The present study was performed to investigate modifications of basal and gonadotrophin-releasing hormone (GnRH)-stimulated (10(-9) mol/l) LH release, induced by 4-h and a 24-h incubation with physiological doses of IGF-I (1, 5 and 10 nmol/l) and IGF-II (5, 10 and 15 nmol/l) in comparison with insulin (0.0017, 0.1722 and 1.722 nmol/l), from primary cultures of male rat anterior pituitary cells. Both during the 4-h and the 24-h incubation, basal and GnRH-stimulated LH release were increased by IGF-I, IGF-II and insulin in a dose-dependent fashion. Present data confirm insulin's capability of potentiating anterior pituitary LH release from dispersed rat anterior pituitary cells in vitro, and reveal similar effects for physiological doses of IGF-I and IGF-II.

Melatonin enhances cortisol levels in aged but not young women.

In spite of animal data showing an effect of melatonin in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, no effect of melatonin on cortisol has been evidenced in young men. Gender and aging are believed to influence the regulation of the HPA axis, and may thus modulate the melatonin effect on cortisol. In this study we investigated whether an effect of melatonin on cortisol can be observed in women of different age. Six young women in early follicular phase (22-32 years; EFW) and eight aged women in postmenopause (54-62 years; PMW) were studied. At 08.00 h on two consecutive days each woman received, randomly and in double-blind fashion, a pill of placebo or melatonin (100 mg). Serum levels of melatonin and cortisol were evaluated at 20-min intervals for 48 h. In comparison to EFW, PMW showed an earlier onset of nocturnal melatonin (p < 0.05) and cortisol rise (p < 0.01) and higher cortisol levels at lunch (p < 0.05) and early evening (p < 0.01). Melatonin administration did not modify serum cortisol levels in EFW but elicited a marked increase of daytime cortisol levels in PMW (p < 0.02). The present data reveal that in aged PMW the cortisol levels are enhanced at selected circadian times and are stimulated by melatonin.

Hypothermic effect of melatonin and nocturnal core body temperature decline are reduced in aged women.

In young humans, the nocturnal rise of the hypothermic hormone melatonin generates 40-50% of the circadian core body temperature (Tc) decline. The nocturnal Tc decline is reduced with aging in men. In this study we investigated whether a similar attenuation occurs in women and whether it is associated with a reduced serum concentration and/or action of melatonin. The circadian rhythms of melatonin and Tc (measured in the vagina) and the responses of both Tc (measured into the auricolar canal) and finger skin temperature to melatonin administration (100 mg at 0800) were investigated in two experiments involving young (22-32 yr) and aged (54-62 yr) women. In aged women, the nocturnal onset of the melatonin rise was phase advanced and Tc decline and Tc rhythm amplitude were reduced (P < 0.0005). The serum melatonin concentrations in aged women were similar to those of young women, but the melatonin capability to reduce Tc and increase skin temperature was markedly impaired. Our data show that, in women, an aging-associated reduction of temperature responses to melatonin is probably involved in inducing an attenuation of the nocturnal Tc decline and circadian Tc rhythm amplitude.

Modification of circadian body temperature rhythm during the luteal menstrual phase: role of melatonin.

In women during early follicular phase (FP), the rise of melatonin at night accounts for 40% of the nocturnal core body temperature (Tc) decline. In seven normal-cycling women, the circadian rhythms of Tc and melatonin of the FP were compared with those of the luteal phase (LP). In addition, in both phases the Tc response to daytime melatonin administration was investigated. Melatonin levels were comparable during the two menstrual phases, but the nocturnal melatonin onset was delayed by 90 min in the LP (P < 0.01). This was accompanied by a delay of the nadir of the Tc circadian rhythm (P < 0.002), a 0.3 degrees C elevation (P < 0.005) of the mean 24-h value, and a 40% blunting (P < 0.002) of the amplitude. This attenuation of circadian Tc in LP women was replicated in two estrogen-treated hypogonadal women by the administration of medroxyprogesterone acetate. The daytime administration of melatonin (2.5 mg) decreased Tc during the FP (P < 0.01) but was ineffective in the LP. Present data indicate that in LP, in association with high progesterone levels, an attenuated and phase-delayed circadian Tc rhythm may, in part, be due to a reduced effect of melatonin.

Exogenous melatonin enhances luteinizing hormone levels of women in the follicular but not in the luteal menstrual phase.

OBJECTIVE: To investigate the effect of exogenous melatonin on LH pulsatility in women during the follicular and luteal menstrual phases. DESIGN: Randomized, double-blind placebo-controlled study. PATIENTS: Normal cycling young women (25 to 35 years old). INTERVENTIONS: Each subject was admitted at the Clinical Research Center for 2 consecutive days on both the follicular and the luteal menstrual phases. On each day, at 7:00 A.M. an indwelling catether was placed in an antecubital vein for a 10 minutes blood sampling from 9:00 A.M. to 5:00 P.M. On the 2 consecutive days of both the follicular and the luteal menstrual phases, each subject randomly received either placebo or melatonin pills (1 mg at 8:00 and 0.75 mg at 10:00 and 12:00 A.M.). MAIN OUTCOME MEASURE: Luteinizing hormone pulsatility. RESULTS: The amplitude of LH pulses and mean LH levels were increased by melatonin in the follicular but not in the luteal menstrual phase. CONCLUSIONS: The stimulatory effect of exogenous melatonin on LH is modulated by the endocrine environment and selectively exerted in the follicular phase of the menstrual cycle.

Modulation of anterior pituitary luteinizing hormone response to gonadotropin-releasing hormone by insulin-like growth factor I in vitro.

OBJECTIVE: To investigate how much insulin-like growth factor I may modulate the LH response to GnRH. DESIGN: In primary cultures of male rat anterior pituitary cells, the LH response to GnRH (10(-9) M) was evaluated after a 24-hour preincubation with medium alone, IGF-I (1, 5, 10, 15 nM), polyclonal antibody anti-IGF-I (Ab-anti-IGF-I), (1:3,000; 1:10,000), or rabbit serum (1:3,000; 1:10,000) as control. MAIN OUTCOME MEASURE: Gonadotropin-releasing hormone-induced LH release from primary cultures of male rat anterior pituitary cells. RESULTS: Insulin-like growth factor I induces a dose-dependent stimulus on the LH response to GnRH. Insulin-like growth factor I at doses of 10 and 15 nM exerted a maximal stimulus, increasing the LH response to GnRH by 30%. The Ab-anti-IGF-I at both dilutions reduced the LH response to GnRH by 30%. No effect was exerted by rabbit serum. CONCLUSIONS: Present data indicate that IGF-I may enhance the normal LH response to GnRH from rat anterior pituitary glands, suggesting important influences of this growth factor in the modulation of anterior pituitary LH release.

Prolonged opioid blockade with naltrexone and luteinizing hormone modifications in women with polycystic ovarian syndrome.

OBJECTIVE: To investigate whether enhanced LH levels of women with polycystic ovarian syndrome (PCOS) are the consequence of an absent hypothalamic opioid inhibitory control and/or an increased sensitivity of gonadotroph to GnRH, induced by sensitizing effects of circulating opioid peptides. DESIGN: Pulsatile LH secretion (10-minute sampling for 6 hours) and GnRH-stimulated (10 micrograms) LH release were investigated in 14 women with PCOS before and after the 5-day administration of placebo (n = 7) or the opioid antagonist naltrexone (50 mg/d; n = 7). Seven age- and weight-matched normal cycling women in follicular phase were used as controls. RESULTS: In comparison with normal cycling women, PCOS showed normal frequency and increased amplitude LH pulses, elevated mean LH levels, and increased LH response to GnRH. In PCOS, placebo administration was not associated with any LH modification, whereas naltrexone enhanced the frequency and decreased the amplitude of LH pulses, without modifying mean LH levels and the LH response to GnRH. CONCLUSIONS: The naltrexone-induced increment of LH frequency revealed a conserved central opioid tone in PCOS. Reduced LH pulse amplitude, induced by naltrexone, was not associated with a reduced LH response to GnRH or with a reduction in mean LH levels. Present data do not support a role for endogenous opioid peptides in the pathogenesis of increased LH levels in PCOS.

Evidence that an altered prolactin release is consequent to abnormal ovarian activity in polycystic ovary syndrome.

OBJECTIVE: To investigate whether endogenous dopaminergic activity is impaired in polycystic ovary syndrome (PCOS)-affected women and is normalized by medical ovariectomy. PATIENTS: Women with PCOS untreated (n = 23) and treated for 3 months with GnRH analogue (GnRH-a) administration (n = 10) and normal cycling young women (n = 23) as controls. INTERVENTIONS: Acute blockade of dopaminergic receptors by the IV administration of 5 mg of the dopaminergic receptor blocking agent sulpiride (sulpiride test) was performed 3 to 7 days after the initiation of spontaneous menses in cycling women or medroxyprogesterone acetate-induced menses in PCOS women. In PCOS women treated with GnRH-a administration (goserelin depot, 3.6 mg SC every 28 days), the sulpiride test was repeated 10 to 15 days after the third GnRH-a administration. MAIN OUTCOME MEASURE: Basal PRL levels and PRL increase induced by sulpiride. RESULTS: Basal PRL levels and the PRL response to sulpiride were increased in women with PCOS. In women with PCOS medical ovariectomy induced by GnRH-a administration reversed to normal both basal and sulpiride-stimulated PRL levels. CONCLUSIONS: In women with PCOS the abnormal regulation of PRL and presumably of hypothalamic neurotransmitters controlling PRL secretion is not a primary alteration but it is likely dependent on abnormal ovarian functionality.

Thermoregulatory and endocrine effects of a low dose of danazol in postmenopausal women: interaction with the effect of naloxone.

Before and on the 30th day of danazol administration (200 mg/day), in six postmenopausal women the activity of endogenous opioid peptides has been indirectly evaluated by the effect on LH secretion and body temperature (measured as rectal temperature) exerted by the infusion of the opioid antagonist naloxone (1.6 mg/h x 4 h preceded by 1.6 mg iv bolus). Before and during danazol administration a GnRH test (100 mcg iv bolus) was also performed to evaluate possible variations in pituitary responsiveness to GnRH. Danazol significantly reduced mean plasma levels of LH and FSH (p less than 0.01), and their response to GnRH stimulus (p less than 0.05). Either before or during danazol administration mean plasma LH and FSH levels did not vary during the infusion of naloxone, while body temperature significantly decreased (p less than 0.01). The decrease in body temperature was significantly greater (p less than 0.05) during danazol than before treatment. The present data suggest that in postmenopausal women a low dose of danazol exerts an antigonadotropic effect mainly reducing the pituitary responsiveness to GnRH. The enhanced hypothermic response to naloxone observed during danazol administration also seems to suggest that in postmenopausal women a low dose of danazol enhances the thermoregulatory role of endogenous opioid peptides.

Effect of sex steroids on body temperature in postmenopausal women. Role of endogenous opioids.

The role of endogenous opioids on the thermoregulatory effect of sex steroids was investigated in six postmenopausal women before and during treatment with transdermal 17 B-estradiol (TTS 50; 50 mcg/day) with or without vaginal progesterone (P4; 100 mg twice daily). In all the different endocrine conditions, saline or the opioid antagonist naloxone (10 mg/hr. preceded by 10 mg iv bolus) were randomly infused for 4 hrs., on two consecutive days. Measurements of body temperature (BT) variations were performed by a thermistor probe placed in the rectum. BT did not significantly vary from baseline values during saline infusion, whereas it significantly decreased during the infusion of naloxone performed, either before treatment (p less than 0.01), during TTS 50 administration (p less than 0.01), or during TTS 50 + P4 (p less than 0.025). The naloxone induced decrease of BT was greater during TTS 50 administration than before treatment (p less than 0.025). The addition of P4 to TTS 50 administration increased baseline BT of 0.4 degrees C (p less than 0.01), and reduced the ability of naloxone to reduce BT (p less than 0.01 vs. TTS 50). The hyperthermic effect of P4 was not abolished by the infusion of naloxone. Our data show that in postmenopausal women the effect of endogenous opioid peptides on BT is enhanced by estradiol and reduced by progesterone. The hyperthermic effect of progesterone does not seem to be mediated by an increased endogenous opioid activity.

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.

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

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 veralipride 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 the hypothermic response to naloxone. Therefore, veralipride seems to increase the activity of endogenous opioid peptides on 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 Parkinson's 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 Parkinson's disease. The low basal body temperature values and the inability of naloxone to exert a hypothermic effect in women suffering from Parkinson's disease seem to constitute further evidence for an impaired regulation of body temperature and impaired activity of the endogenous opioid system in this pathology.

Neuroendocrine and clinical effects of transdermal 17 beta-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.

Role of goserelin-depot in the clinical management of uterine fibroids.

On 30 women suffering from uterine fibroids, the monthly subcutaneous administration of goserelin depot (3.6 mg) for 6 (n = 22) or 12 months (n = 8) induced an about 50% shrinkage of uterus and fibroid volume, and within 3 months, an increase in the haematocrit value, with no metabolic side effects or detectable bone demineralization, evaluated by single photon absortiometry at distal radius. Both uterine and fibroid volumes reversed to pretreatment values after 3 months of goserelin depot withdrawal. In comparison with untreated subjects, on another 10 patients a three month administration of goserelin depot reduced the loss of blood during the surgical removal of the uterus or fibroids. Present data indicate that goserelin depot is effective and relatively safe in the medical management of uterine fibroids. Although, goserelin depot cannot yet be proposed as a definite medical therapy, it may represent a useful instrument in the presurgical management of uterine fibroids.