Estrous cycle and stress: influence of progesterone on the female brain

Abstract

The female brain operates in a constantly changing chemical milieu caused by cyclical changes in gonadal hormones during the estrous cycle (menstrual cycle in women). Such hormones are highly lipophilic and pass readily from the plasma to the brain where they can influence neuronal function. It is becoming clear that the rapid reduction in peripheral circulating progesterone, which occurs during the late diestrous phase of the cycle, can trigger a withdrawal-like response, in which changes in GABAA receptor expression render hyper-responsive certain brain areas involved in processing responses to stressful stimuli. The periaqueductal gray matter (PAG) is recognised as an important region for integrating anxiety/defence responses. Withdrawal from progesterone, via actions of its neuroactive metabolite allopregnanolone, triggers up-regulation of extrasynaptic GABAA receptors on GABAergic neurons in the PAG. As a consequence, ongoing GABAergic tone on the output cells decreases, leading to an increase in functional excitability of the circuitry and enhanced responsiveness to stressful stimuli during the late diestrous phase. These changes during late diestrus could be prevented by short-term neurosteroid administration, timed to produce a more gradual fall in the peripheral concentration of allopregnanolone than the rapid decrease that occurs naturally, thus removing the trigger for the central withdrawal response.

The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders

“…The most severe symptoms are reported during the luteal phase when progesterone levels rise and then begin to fall (Lovick 2012). Thus, the pathophysiology of PMS/PMDD is thought to involve a reduction in the levels of neurosteroids.…”

“…PMS patients also show a reduced sensitivity to pregnanolone in the luteal phase (Sundstrom et al 1998) which may reflect altered regulation of steroidogenenic enzymes over the menstrual cycle. Administration of the SSRI fluoxetine reduces symptom severity in PMS/PMDD sufferers possibly by increasing the activity of the steroidogenic enzyme 3α-HSD and allopregnanolone production independently of the 5HT system (Griffin and Mellon 1999; Lovick 2012; Marjoribanks et al 2013; Pinna et al 2009). Increased allopregnanolone production and a more gradual drop in steroid levels in the late luteal phase may help reduce the anxiogenic effects observed following rapid steroid withdrawal (Lovick 2012).…”

“…One explanation for the anxiogenic actions of neurosteroids over the estrous cycle is that, at low concentrations, neurosteroids preferentially act at inhibitory interneuron populations, reducing their output and increasing the excitability of their target neurons (Backstrom et al 2013; Lovick 2012; Wang 2011). Indeed, it has been suggested that increased expression of α 4 βδ receptors in GABAergic neuronal populations in the PAG following periods of elevated progesterone results in disinhibition of the principal output neurons and increased network excitation (Brack and Lovick 2007; Griffiths and Lovick 2005a; Griffiths and Lovick 2005b; Lovick 2012).…”

Periaqueductal Gray

“…It also receives inputs from the lateral part of the intermediate and deep layers of the superior colliculus, a region from which orienting and approach movements to stimuli in the lower visual field are evoked (Redgrave et al, 1993). On balance, these anatomical inputs to the rlPAG likely provide the contextual and sensory (visual and chemosensory) signals necessary for the regulation and expression of predatory related behaviors (Sukikara et al, 2006;Mota-Ortiz et al, 2009, 2012.…”

“…For example, the oestrus cycle modulates PAG function through actions on inhibitory GABAergic transmission (Lovick, 2008(Lovick, , 2012Devall et al, 2011), injury triggers both longterm (Laprairie and Murphy, 2009), and short-term (Mor et al, 2011) structural changes in distinct PAG columns, each of which likely contributes to altered somatomotor, cardio-respiratory and analgesic coping responses.…”