Figure 1
  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.
  2. 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.
  3. 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).