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 GABA(A) 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 GABA(A) 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.

Figures

Figure 1.. Schematic drawing showing the functional consequences of increased α4β1δ GABAA receptor expression in the periaqueductal gray matter (PAG). A, When expression of α4β1δ receptors is low, spontaneous activity in GABAergic interneurones in the PAG limits the excitability of the output neurones. B, Increased expression of α4β1δ receptors when progesterone levels fall in late diestrous leads to an increase in tonic current carried by GABAergic cells, which limits their ongoing activity. The output neurones therefore become intrinsically more excitable, and the threshold for activation by stressful stimuli is lowered. Reproduced from Ref. with permission.

Figure 2.. A, Change in latency of the tail flick reflex (s) following exposure to 5-min anxiogenic vibration stress in rats at different stages of the estrous cycle. Data (mean ± SEM) are reported as change in tail flick latency (TFL) from baseline in 6-min post-vibration stress. B, Density of Fos-positive neurons in the periaqueductal gray matter (PAG) of rats exposed to anxiogenic stress and tail flick testing at different stages of the estrous cycle. P = proestrus; E = estrus; ED = early diestrus; LD = late diestrus. Figure drawn from data in Ref. and reproduced with permission. *P < 0.05, **P < 0.01 (post hoc Bonferroni test) stressed group compared to the non-stressed group after significant (P < 0.05) one-way ANOVA. §§P < 0.01 LD stressed group compared to stressed rats at all other stages of the estrous cycle (post hoc Bonferroni test).

Figure 3.. Schematic presentation of the rationale behind short-term neurosteroid replacement to prevent development of progesterone withdrawal-evoked anxiogenesis during late diestrus. A, At late diestrus, the fall in brain concentration of progesterone and its neuroactive metabolite allopregnanolone (ALLO) triggers a withdrawal syndrome manifested as an increased responsiveness to stress. B, Short-term dosing with a steroidogenic agent in the evening of early diestrus should raise plasma and hence brain allopregnanolone transiently and so blunt the rapid fall in allopregnanolone that normally occurs during late diestrus. The trigger for development of the withdrawal syndrome should be removed.

Figure 4.. A, Short-term dosing with fluoxetine (1.75 mg/kg) on the evening of late diestrus, with a top up on the morning of late diestrus, prevents the development of stress-induced hyperalgesia during late diestrus (decrease in tail flick latency (TFL) compared to naive non-stressed rats). White bars = non-stressed rats; light gray bars = stressed vehicle-treated rats; dark gray bars = stressed fluoxetine-treated rats. B, Fluoxetine administration also prevented the reduction in stress-induced functional deactivation in the periaqueductal gray matter (PAG) (decrease in density of Fos-positive neurons in the PAG compared to naive non-stressed rats; Devall AJ and Lovick TA, unpublished results). *P < 0.05 compared to vehicle-treated rats in late diestrus (oneway ANOVA followed by the Bonferroni test).