Progesterona e sono profundo e reparador

Propriedades da progesterona em sua condição de neuroesteroide ativo e protetor do sistema nervoso e ... do sono

[Este artigo já foi publicado no nosso antigo blog do substack ao qual, recentemente,me foi vetado o acesso para postar novas publicações. Dessa forma e para que possa ser conhecido pelos leitores deste novo blog -intitulado outramedicina2024.substack.com - , faço aqui a republicação do artigo]

Em outras notas foram examinadas as alterações hormonais que ocorrem na madrugada [a exemplo do aumento do cortisol e outros hormônios do estresse], durante o nosso sono como também o papel do glicogênio, da tireoide e dos hormônios protetores na garantia de um sono profundo e reparador.

Voltamos ao tema, agora tomando a progesterona e seu papel – pouquíssimo mencionado na medicina – na proteção do nosso sono, homens e mulheres.

Estudo randomizado e duplo cego em homens e em mulheres, estas na menopausa [FRIESS, 1997], claramente documentou aumentos significativos na fase do sono chamada de REM [movimentos rápidos nos olhos][D] com uso da progesterona. E também menos interrupção do sono [A].

[REM - O sono reparador depende do número de horas e da qualidade do sono, por exemplo, poucas interrupções. Uma das fases do sono é a do REM - rapid eye movements - ou do rápido movimento dos olhos. Ela ocupa tipicamente ¼ do tempo total do sono em adultos e sua parte mais profunda se dá tardiamente na noite. Vem acompanhada de ereções noturnas do pênis ou do clitóris; e de sonos vívidos. A fase REM é essencial para a boa saúde].

De tal forma, que a progesterona é um tratamento efetivo e baseado em evidências para distúrbios do sono [A][B], mesmo que estes incluam suores noturnos e, na perimenopausa, ondas de calor [Ver notas no blog sobre menopausa e progesterona].

O estudo de Schussler [2008], duplo cego, em mulheres saudáveis pós-menopausadas, resultando em uma evidente melhora no sono. Elas despertaram menos vezes, o REM aumentou e provavelmente houve um mecanismo via GABA [GABA-agonístico][A].

Outro estudo demonstrou resultado semelhante em favor do sono [B]. E concluiu que a progesterona restaurou o sono normal [quando ele estava prejudicado antes do uso da progesterona].

E “restaurou o sono normal [ao contrário dos hipnóticos disponíveis no mercado, que tendem a inibir o sono profundo], agindo como um regulador ´fisiológico´ do sono muito mais do que como uma droga hipnótica. O uso da progesterona pode trazer novas estratégias terapêuticas no tratamento dos distúrbios do sono, em particular no envelhecimento quando o sono é fragmentado e de baixa qualidade”[B].

Já foi sugerido, em pesquisas, que esse efeito da progesterona [melhora do tempo de sono] é mediado por seus metabólitos neuroativos que interagem com o sistema GABA [C], a exemplo da alopregnenolona [G]. Os efeitos hipnóticos da progesterona são ativos através – como foi mencionado - dos receptores do sistema GABA.

Vários metabólitos neuroativos da progesterona produzem efeitos sedativos. E foi já demonstrado os efeitos positivos da alopregnenolona sobre o sono, efeitos de perfil benzodiazepínico. Também se sabe dos efeitos neuroprotetores da alopregnanolona em caso de lesão isquêmica e neuropatia periférica [diabetes, por exemplo]. Este metabólito tornou-se um “potencial candidato para o tratamento de desordens do humor e ansiedade” e em desordens neuropsiquiátricas [G].

Digamos que, no mínimo, a progesterona - em todos os sentidos o grande antiestressor durante a gestação -, possui propriedades sedativas e protetoras do sistema nervoso que representam mais uma grande oportunidade terapêutica que a medicina oficial deixa de utilizar e, com isso, deixa de amenizar a dor e o sofrimento de milhões. Sempre favorecendo, na prática, as drogas tóxicas e patenteadas da Big Pharma. Dessa forma deixando de seguir a ciência quando ela não traz tanto retorno de capital.

G Dantas [Publicado originalmente em Brasília, 2-7-24]

As informações aqui presentes não pretendem servir para uso diagnóstico, prescrição médica, tratamento, prevenção ou mitigação de qualquer doença humana. Não pretendem substituir a consulta ao profissional médico ou servir como recomendação para qualquer plano de tratamento. Trata-se de informações com fins estritamente educativos. Nenhuma das notas aqui presentes, neste blog, conseguirá atingir o contexto específico do paciente singular, nem doses, modo de usar etc. Este trabalho compete ao paciente com seu médico. Isso significa que nenhuma dessas notas - necessariamente parciais - substitui essa relação.

Referências ________________

[A] SCHUSSLER P KLUGE M YASSOURIDIS A, 2008. Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women. Psychoneuroendocrinology. 2008 Sep;33(8):1124-31. doi: 10.1016/j.psyneuen.2008.05.013. Epub 2008 Aug 3. PMID: 18676087 DOI: 10.1016/j.psyneuen.2008.05.013 “Sleep is frequently impaired in postmenopausal women. Progesterone prompted benzodiazepine-like effects on sleep EEG in young normal male subjects. Aim of this study was to test if treatment with progesterone improves sleep after menopause. A randomised double blind crossover design study with 2 treatment intervals of 21 days duration separated by a 2 weeks washout was performed. An oral dose of 300 mg micronized progesterone was given each for 21 days. At the beginning and the end of the two intervals a sleep EEG was recorded and cognitive performance was assessed in 10 healthy postmenopausal women (age: 54-70 years). Progesterone treatment led to a decrease of intermittent time spent awake. During the first third of the night rapid eye movement (REM) sleep increased. The spectral analysis of the EEG resulted in no significant differences of the power spectra. Progesterone did not affect cognitive performance. In summary progesterone demonstrated a distinct sleep promoting effect by reduction of time of wake without impairing cognitive functions during daytime. As possible mechanisms of progesterone a GABA-agonistic effect and the regulation of gene expression via the progesterone receptor are discussed. Progesterone might be useful in the treatment of sleep disturbances of postmenopausal women”.

[B] CAUFRIEZ A LEPROULT R, 2010. Progesterone prevents sleep disturbances and modulates GH, TSH, and melatonin secretion in postmenopausal women. J Clin Endocrinol Metabolism. 2011 Apr;96(4):E614-23. doi: 10.1210/jc.2010-2558. Epub 2011 Feb 2. PMID: 21289261 DOI: 10.1210/jc.2010-2558 “Context: A number of neuroactive progesterone metabolites produce sedative-like effects. However, the effects of progesterone administration on sleep are not well characterized.

Objective: To investigate the effects of a 3-wk progesterone administration on sleep architecture and multiple hormonal profiles.

Subjects: Eight healthy postmenopausal women, 48-74 yr old, without sleep complaints or vasomotor symptoms. None was on hormone replacement therapy. They did not take any medication for ≥ 2 months.

Design: Randomized, double-blind, placebo-controlled study. For 3 wk, subjects took daily at 2300 h a capsule of either 300 mg of progesterone or placebo. Sleep was polygraphically recorded during the last two nights, and blood samples were obtained at 15-min intervals for 24 h.

Results: During the first night (no blood sampling), sleep was similar in both conditions. Under placebo, blood sampling procedure was associated with marked sleep disturbances, which were considerably reduced under progesterone treatment: mean duration of wake after sleep onset was 53% lower, slow-wave sleep duration almost 50% higher, and total slow-wave activity (reflecting duration and intensity of deep sleep) almost 45% higher under progesterone than under placebo (P ≤ 0.05). Nocturnal GH secretion was increased, and evening and nocturnal TSH levels were decreased under progesterone (P ≤ 0.05).

Conclusions: Progesterone had no effect on undisturbed sleep but restored normal sleep when sleep was disturbed (while currently available hypnotics tend to inhibit deep sleep), acting as a "physiologic" regulator rather than as a hypnotic drug. Use of progesterone might provide novel therapeutic strategies for the treatment of sleep disturbances, in particular in aging where sleep is fragmented and of lower quality”.

[C] FRIESS E TAGAYA H TRACHSEL L, 1997. Progesterone-induced changes in sleep in male subjects. Am J Physiol. 1997 May;272(5 Pt 1):E885-91. doi: 10.1152/ajpendo.1997.272.5.E885. PMID: 9176190 DOI: 10.1152/ajpendo.1997.272.5.E885 “Progesterone administration induces a reduction of the vigilance state in humans during wakefulness. It has been been suggested that this effect is mediated via neuroactive metabolites that interact with the gamma-aminobutyric, acidA (GABAA) receptor complex. To investigate the effects of progesterone administration on the sleep electroencephalogram (EEG) in humans we made polysomnographic recordings, including sleep stage-specific spectral analysis, and concomitantly measured plasma concentrations of progesterone and its GABA-active metabolites 3 alpha-hydroxy-5 alpha-dihydroprogesterone (allopregnanolone) and 3 alpha-hydroxy-5 beta-dihydroprogesterone (pregnanolone) in nine healthy male subjects in a double-blind placebo-controlled crossover study. Progesterone administration at 9:30 PM induced a significant increase in the amount of non-rapid eye movement (REM) sleep. The EEG spectral power during non-REM sleep showed a significant decrease in the slow wave frequency range (0.4-4.3 Hz), whereas the spectral power in the higher frequency range (> 15 Hz) tended to be elevated. Some of the observed changes in sleep architecture and sleep-EEG power spectra are similar to those induced by agonistic modulators of the GABAA receptor complex and appear to be mediated in part via the conversion of progesterone into its GABA-active metabolites”.

[D] “Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream vividly. The REM phase is also known as paradoxical sleep (PS) and sometimes desynchronized sleep or dreamy sleep,^[1] because of physiological similarities to waking states including rapid, low-voltage desynchronized brain waves. Electrical and chemical activity regulating this phase seem to originate in the brain stem, and is characterized most notably by an abundance of the neurotransmitter acetylcholine, combined with a nearly complete absence of monoamine neurotransmitters histamine, serotonin and norepinephrine.^[2]

REM and non-REM sleep alternate within one sleep cycle, which lasts about 90 minutes in adult humans. As sleep cycles continue, they shift towards a higher proportion of REM sleep.. REM sleep occurs 4 times in a 7-hour sleep. REM sleep is called "paradoxical" because of its similarities to wakefulness. Although the body is paralyzed, the brain acts as if it is somewhat awake, with cerebral neurons firing with the same overall intensity as in wakefulness. During REM sleep, electrical connectivity among different parts of the brain manifests differently than during wakefulness. Frontal and posterior areas are less coherent in most frequencies, a fact which has been cited in relation to the chaotic experience of dreaming. However, the posterior areas are more coherent with each other; as are the right and left hemispheres of the brain, especially during lucid dreams. Brain energy use in REM sleep, as measured by oxygen and glucose metabolism, equals or exceeds energy use in waking. The rate in non-REM sleep is 11–40% lower.

The eye movements themselves may relate to the sense of vision experienced in the dream,^[31] but a direct relationship remains to be clearly established. Congenitally blind people, who do not typically have visual imagery in their dreams, still move their eyes in REM sleep. An alternative explanation suggests that the functional purpose of REM sleep is for procedural memory processing, and the rapid eye movement is only a side effect of the brain processing the eye-related procedural memory. Heart rate, cardiac pressure, cardiac output, arterial pressure, and breathing rate quickly become irregular when the body moves into REM sleep.^{[29]: 12–15} In general, respiratory reflexes such as response to hypoxia diminish.

Erections of the penis (nocturnal penile tumescence or NPT) normally accompany REM sleep in rats and humans.^{[34]: 169–173} If a male has erectile dysfunction (ED) while awake, but has NPT episodes during REM, it would suggest that the ED is from a psychological rather than a physiological cause. In females, erection of the clitoris (nocturnal clitoral tumescence or NCT) causes enlargement, with accompanying vaginal blood flow and transudation (i.e. lubrication). During a normal night of sleep, the penis and clitoris may be erect for a total time of from one hour to as long as three and a half hours during REM.

The organism returns to homeostatic regulation almost immediately after REM sleep ends. During a night of sleep, humans usually experience about four or five periods of REM sleep; they are shorter (~15 min) at the beginning of the night and longer (~25 min) toward the end. Many animals and some people tend to wake, or experience a period of very light sleep, for a short time immediately after a bout of REM. The relative amount of REM sleep varies considerably with age. A newborn baby spends more than 80% of total sleep time in REM. REM sleep typically occupies 20–25% of total sleep in adult humans: about 90–120 minutes of a night's sleep. The first REM episode occurs about 70 minutes after falling asleep. Cycles of about 90 minutes each follow, with each cycle including a larger proportion of REM sleep”.

[E] LANCEL M FAULHABER J HOLSBOER F, 1996. Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators. Am J Physiol. 1996 Oct;271(4 Pt 1):E763-72. doi: 10.1152/ajpendo.1996.271.4.E763. PMID: 8897866 DOI: 10.1152/ajpendo.1996.271.4.E763 “There is much evidence that progesterone has hypnotic anesthetic properties. In this vehicle-controlled study, we examined the effects of three doses of progesterone (30, 90, and 180 mg/kg) administered intraperitoneally at light onset on sleep in rats. Progesterone dose dependently shortened non-rapid eye movement sleep (NREMS) latency, lengthened rapid eye movement sleep (REMS) latency, decreased the amount of wakefulness and REMS, and markedly increased pre-REMS, an intermediate state between NREMS and REMS. Progesterone also elicited dose-related changes in sleep state-specific electroencephalogram (EEG) power densities. Within NREMS, EEG activity was reduced in the lower frequencies (< or = 7 Hz) and was enhanced in the higher frequencies. Within REMS, EEG activity was markedly enhanced in the higher frequencies. The effects were maximal during the first postinjection hours. The concentrations of progesterone and the progesterone metabolites 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one, both positive allosteric modulators of gamma-aminobutyric acid A (GABAA) receptors, were determined at different time intervals after vehicle and 30 or 90 mg/kg progesterone. Progesterone administration resulted in dose-dependent initially supraphysiological elevations of progesterone and its metabolites in the plasma and brain, which were most prominent during the first hour postinjection. The effects of progesterone on sleep closely resemble those of agonistic modulators of GABAA receptors such as benzodiazepines and correlate well with the increases in the levels of its GABAA agonistic metabolites. These observations suggest that the hypnotic effects of progesterone are mediated by the facilitating action of its neuroactive metabolites on GABAA receptor functioning”.

[F] LANCEL M FAULHABER J, 1997. Allopregnanolone affects sleep in a benzodiazepine-like fashion. J Pharmacol Exp Ther. 1997 Sep;282(3):1213-8 PMID: 9316828 “Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-rapid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone significantly increased the time spent in pre-REMS, an intermediate state between non-REMS and REMS. Furthermore, allopregnanolone dose-dependently influenced EEG activity during non-REMS and REMS. In non-REMS, EEG activity was decreased in the lower frequencies (< or =7 Hz) and enhanced in the frequencies of > or =13 Hz. In REMS, allopregnanolone enhanced high-frequency EEG activity (> or =17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep”.

[G] MELCANGI R C PANZICA G C, 2014. Allopregnanolone: state of the art. Prog Neurobiol. 2014 Feb:113:1-5. doi: 10.1016/j.pneurobio.2013.09.005. Epub 2013 Oct 10 PMID: 24121112 DOI: 10.1016/j.pneurobio.2013.09.005 “Allopregnanolone, a neuroactive steroid derived from progesterone, is synthesized within the nervous tissue, by means of specific enzymes. Contrary to progesterone and its first metabolite dihydroprogesterone, allopregnanolone is able to interact with GABA-A receptor and not with the classical progesterone receptor. This suggests that the effect of progesterone administration may be due to activation of progesterone receptor, or of GABA-A receptor, or both. However, this is rarely considered in the experimental studies. Here we summarize and discuss the hot topics involving the actions of allopregnanolone within the nervous tissue. One major role of this neuroactive steroid is neuroprotection in case of lesion, ischemia or peripheral neuropathies (i.e., diabetes). In addition, allopregnanolone may reduce the symptoms of neurodegenerative diseases (e.g., Alzheimer, Parkinson, Niemann-Pick type C, multiple sclerosis) in animal models and now translational studies are developed for its therapeutic use. Allopregnanolone may exert a beneficial effect also in case of neuropathic pain and it is also a potential candidate for the treatment of mood and anxiety disorders. Finally, this neuroactive steroid seems to have important physiological roles in the early differentiation of some neural circuits (in particular at hippocampal level), and to reduce stress during pregnancy. In conclusion, it appears that allopregnanolone is a key regulator of physiological functions and may have interesting therapeutic perspectives for neurodegenerative and psychiatric disorders".

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