B

2300-0100 h

Fig. 8. Effects of 300 mg progesterone administration on EEG power spectra during non-REM sleep of (A) the total night and (B) four consecutive 2-h periods of night sleep. Data represent the mean (± SE) deviation from placebo condition (= 100%, depicted by the zero reference line). Bars below the abscissa indicate the significance levels of treatment effects compared to the placebo condition (filled bar: p < 0.05, open bar: p < 0.10, MANOVA for repeated measures, n = 9). (Adapted with permission from ref. 76.)

i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—r

Fig. 8. Effects of 300 mg progesterone administration on EEG power spectra during non-REM sleep of (A) the total night and (B) four consecutive 2-h periods of night sleep. Data represent the mean (± SE) deviation from placebo condition (= 100%, depicted by the zero reference line). Bars below the abscissa indicate the significance levels of treatment effects compared to the placebo condition (filled bar: p < 0.05, open bar: p < 0.10, MANOVA for repeated measures, n = 9). (Adapted with permission from ref. 76.)

in rats (75) and humans (76). For example, during non-REM sleep (Fig. 8) the slow-wave EEG activity in the delta frequency range declined progressively to a significant decrease between 3 and 5 am (p < 0.01) and was still reduced in the last 2 h of the night following oral administration of micronized progesterone. Similarly, the spectral power in the theta range declined significantly between 3 and 5 am (p < 0.02). In contrast, the EEG

activity in the beta frequency range tended to increase during the same time span (p < 0.07). Progesterone administration induced changes in sleep architecture and sleep-EEG power spectra (76) that are comparable with the well-established effects of agonistic ligands at the GABAa receptor complex: suppression of REM sleep, an increase in non-REM sleep and especially stage 2 sleep, a prolonged decrease in non-REM sleep-EEG activity in the slow wave frequency range and the largely sleep-stage-independent increase in the spectral power in the higher frequencies of the beta range (>15 Hz) (35,77-79). Within the same study, the effects of PROG administration on sleep could be clearly separated from sedative effects (80) following progesterone administration, for which much higher dosages were usually required (73). In addition, spectral analysis of the sleep EEG during the course of pregnancy revealed a progressive reduction of the EEG spectral power, with the largest changes in the spindle frequency range (81); the variations of the spectral power in the upper sigma frequency range have been shown to be related to the menstrual cycle (82).

To date, clinical studies concerning anxiolytic effects of PROG administration are lacking. However, animal studies suggest that potential anxiolytic effects of PROG administration might be gender-specific (66,83) and are probably related to an augmentation of GABAAreceptor functioning (66,67). Although PROG administration has been shown to have a clinical benefit in female patients suffering from PMS (84), no relationship could be demonstrated between CSF levels of progesterone or neurosteroids and clinical symptoms in these patients (63). Moreover, in a recently conducted clinical study, there was no significant reduction in symptoms of a benzodiazepine withdrawal following PROG administration (85).

In conclusion, PROG administration may constitute a valuable new therapeutic strategy for various neuropsychiatric disorders. For example, natural PROG may be considered as an alternative to synthetic analogs if an additional agonistic modulation of the GABA-benzodiazepine receptor complex is desired during therapy with progestins. However, the systemic effects of PROG administration are highly complex and may not be simply related to a general increase of GABAA receptor functioning.

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