Figure 1
- Estradiol, progesterone and allopregnanolone play important
physiological functions by modulating inflammatory processes and
behavior. In healthy pregnant women, circulating concentrations of
Estradiol progesterone and allopregnanolone rise drastically during
pregnancy before decreasing dramatically following childbirth (10-12).
Progesterone reaches a 100-fold higher concentration compared to
baseline at 36 weeks of pregnancy. Estradiol and allopregnanolone
concentrations closely parallel progesterone level increase during
pregnancy and decline in the early postpartum period (11). Their
concentrations increase mainly from the first to the second trimester,
and then remain relatively elevated until after delivery. This
hormonal progression during pregnancy is consistent with a
physiological role of these reproductive steroids as hormonal modifier
in pregnancy and postpartum pathophysiological processes (13).
Allopregnanolone acts as a positive allosteric modulator of the
inhibitory action of GABA at GABAA receptors, which
has been recently associated with rapid and long-lasting improvement
of postpartum depression (13).Recent reports found that
COVID-19-positive pregnant patients appeared asymptomatic upon
admission to the obstetrical service. However, immediately after
delivery, they developed severe COVID-19 symptoms, which in some women
required ICU admission (4-6). This scenario suggests that in pregnant
women infected by SARS-CoV-2, reproductive steroids may provide a
beneficial action. Appearance of symptoms in these patients occurred
at the same time that levels of estradiol, progesterone and
allopregnanolone decline postpartum. These hormones play an important
role in regulating inflammatory processes by inhibiting
pro-inflammatory markers and reshaping competence of immune cells. It
is conceivable that they protect from COVID-19 symptoms during
pregnancy. The hypothesis that these reproductive steroids may offer a
valuable COVID-19 treatment in men and women should be verified in
clinical trials.
- Schematic representation of toll-like receptor 4 (TLR4) signaling and
cross-link with allopregnanolone. In macrophages, the (TLR4-specific
ligand, lipopolysaccharide (LPS), induces proinflammatory cytokines
and chemokines (27). Monocytes and macrophages were studied as a model
of peripheral immune signaling activation (27) showing LPS activated
the TLR4 pathway with downstream activation of nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-kB) and increased
pro-inflammatory mediators (MCP-1 and TNF-α). Peripheral inflammation
also signals to the brain with production of pro-inflammatory
responses. However, TLR4 signal cascade is also expressed in neurons.
Allopregnanolone acts as a positive allosteric modulator of the action
of GABA at GABAA receptors and in brain mediates tonic
inhibition (14-16), which has been recently, associated with rapid and
long-lasting improvement of symptoms of postpartum depression in 70%
of women (13). Furthermore, allopregnanolone can also dampen
inflammation by acting at GABAA receptor expressed in
neuroimmune cells, including macrophages, lymphocytes and glial cells.
GABAA receptor forms a complex with TLR4 followed by
an intracellular signal and activated (phosphorylated) transcription
factors that translocate to the nucleus where they induce the
synthesis of various proinflammatory markers, such as TNF-α. However,
allopregnanolone by inhibiting the GABAAreceptor-containing α2 subunit/TLR4 complex formation alters the
intracellular signaling with a mechanism that involves blockade of
TLR4/MD-2 protein interactions in macrophages that ultimately reduced
production of pro-inflammatory mediators through NF-κB-dependent or
NFκB-independent signaling pathways (27). This effect was also
demonstrated in the brain. Hence, inhibition of pro-inflammatory
processes both in the peripheral and neuroimmune signaling, which can
be initiated by allopregnanolone binding at GABAAreceptor in monocytes, macrophages and brain cells, underscores the
anti-inflammatory effects of allopregnanolone and underlies its novel
function to regulate periphery and brain immune responses.
- Schematic representation of immunomodulatory effects of progesterone.
In the periphery, progesterone directly regulates T cell activation
and differentiation by: 1) T cell activation; 2) Inducing tolerance;
3) Cytotoxicity; and 4) Inducing tolerance at maternal fetal
interface. Modified from (30).