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Background Premenstrual dysphoric disorder (PMDD) is common, with at least 3% of the female population affected by one or more of the typical mood symptoms of depression, irritability, mood swings and anxiety. The cyclicity and close relationship to the luteal phase of the menstrual cycle is characteristic for this syndrome and positive allosteric modulators (PAMs) on the GABAA receptor, especially allopregnanolone, are believed to be involved in the symptomatology.

Aim To summarise the research on the role of PAMs and other neuroactive steroids in the pathophysiology of PMDD.

Method PubMed was searched for articles including the terms Premenstrual syndrome, AND neurosteroids OR allopregnanolone OR GABA OR oestradiol. Many additional publications were previously known to the authors and basic animal research was covered in a secondary step through reference lists.

Results There is evidence that allopregnanolone, like other PAMs of the GABAA receptor, is sedative in high concentrations and, in a minor proportion of the population, causes anxiety and irritability at lower levels, pointing to an inter-individual difference in sensitivity. In research comparing women with PMDD and healthy controls, differences in brain function and subcomposition of GABAA receptors related to levels of allopregnanolone have been found. Also, the varying levels of neuroactive steroids in general seem to worsen the symptoms. Supressed ovulation is effective but add-back hormones are necessary to prevent severe side-effects and could cause adverse mood in these individuals.

Conclusions There is yet no effective treatment for PMDD available. Allopregnanolone seems to be a key provocateur of PMDD symptoms in susceptible individuals. Future research should focus on interventions that interfere with the effects of neurosteroids or the plasticity of the GABAA receptor itself.

Allopregnanolone (allo) and isoallopregnanolone (isoallo) are neuroactive steroid epimers that differ in hydroxyl orientation at carbon three. Allo is a potent GABA-A receptor agonist, while isoallo acts as an antagonist, influencing brain function through their interconversion. Their metabolism varies across brain regions due to enzyme distribution, with AKR1C1–AKR1C3 active in the brain and AKR1C4 restricted to the liver. In rats, AKR1C9 (liver) and AKR1C14 (intestine) perform similar roles. Beyond AKR1Cs, HSD17Bs regulate steroid balance, with HSD17B6 active in the liver, thyroid, and lung, while HSD17B10, a mitochondrial enzyme, influences metabolism in high-energy tissues. Our current data obtained using the GC-MS/MS platform show that allo and isoallo in rats undergo significant metabolic conversion, suggesting a regulatory role in neurosteroid action. High allo levels following isoallo injection indicate brain interconversion, while isoallo clears more slowly from blood and undergoes extensive conjugation. Metabolite patterns differ between brain and plasma—allo injection leads to 5α-DHP and isoallo production, whereas isoallo treatment primarily yields allo. Human plasma contains mostly sulfate/glucuronided steroids (2.4–6% non-sulfate/glucuronided), whereas male rats exhibit much higher free steroid levels (29–56%), likely due to the absence of zona reticularis. These findings highlight tissue-specific enzymatic differences, which may impact neurosteroid regulation and CNS disorders.

Problem: Various chemokines have been linked to endometriosis. Notably, chemokines such as CCL2, CXCL8, and CXCL1 have also been shown to promote nociception. In this study, we investigated whether increased serum concentrations and endometrial expression of chemokines (specifically CCL2, CXCL8, and CXCL1) are associated with heightened severity of pain symptoms in women with endometriosis.

Method of Study: The study included women with endometriosis (with [n = 27] and without [n = 24] hormonal treatment) as well as healthy controls (n = 22). All participants underwent blood sampling and an endometrial biopsy during the secretory phase of the menstrual cycle. Symptom severity in the patient group was assessed using the pain dimension of the Endometriosis Health Profile 30 (EHP-30) and a visual analog scale (VAS) for pain.

Results: Serum levels of CCL2 and CXCL1, as well as endometrial expression of CXCL8, were lower in women with endometriosis compared to controls. Furthermore, increased serum levels of CCL2, CXCL8, and CXCL1 were associated with higher EHP-30 pain domain scores in women with endometriosis. Similarly, elevated endometrial expression of CXCL8 and CXCL1 correlated with higher VAS scores. Notably, when the patient group was stratified based on ongoing hormonal treatment, CXCL1 emerged as the most promising target, with both increased serum concentration and endometrial expression consistently being associated with greater symptom severity.

Conclusions: Our results suggest that chemokines, particularly CXCL1, are associated with greater pain severity and reduced quality of life in women with endometriosis. However, these correlations do not establish causality and should be interpreted with caution.

Background and Objectives: Neuroinflammation plays a significant role in liver and neurological disorders via its disruption of neurotransmission, which alters cerebral function, resulting in cognitive and motor impairment, fatigue, anxiety, and depression. A key interaction exists between GABAergic neurotransmission and neuroinflammation, whereby excessive GABA_A receptor activation exacerbates cognitive and behavioural impairment. Golexanolone, a novel GABA_A-receptor-modulating steroid antagonist (GAMSA), primarily attenuates GABAergic potentiation via GABA_A-positive steroid allosteric receptor modulators such as allopregnanolone. This review aims to summarize new evidence showing that golexanolone improves peripheral inflammation, neuroinflammation, and neurological alterations in animal models of different neurological pathologies. We provide an overview of the first clinical trial using this novel compound.

Results: In rat models of hyperammonemia and minimal hepatic encephalopathy (MHE), peripheral inflammation induces microglia and astrocyte activation and neuroinflammation, altering GABAergic neurotransmission and resulting in cognitive and motor impairment. Golexanolone's unique dual action reduces peripheral inflammation and glial activation, thus normalizing neurotransmission and cognitive and motor function. Furthermore, a phase II study in cirrhotic patients with MHE shows that golexanolone is well tolerated and improves cognition. Similarly, in a model of primary biliary cholangitis (PBC) involving bile-duct ligation, peripheral inflammation, neuroinflammation, and altered neurotransmission—associated with fatigue, impaired memory, and locomotor gait and motor incoordination—were reversed by the dual action of golexanolone. In the Parkinson's disease (PD) rat model induced by neurotoxin 6-OHDA, rats exhibited fatigue, anhedonia, impaired memory, and locomotor gait and motor incoordination, which were associated with microglia and astrocyte activation in the substantia nigra and striatum, in addition to tyrosine hydroxylase (TH) loss. Golexanolone reduces microglia and astrocyte activation, partially reduces TH loss, and improves fatigue, anhedonia, memory, locomotor gait, and motor incoordination. Golexanolone also normalizes elevated levels of α-synuclein.

Conclusions: These findings suggest that golexanolone has beneficial therapeutic effects for treating fatigue, depression, motor, and cognitive impairment across diverse neuroinflammatory conditions, including synucleinopathies.

Objective: The mechanisms behind endometriosis-related pain are not yet fully understood. To determine if there is a difference in the density of endometrial nerve fibers between women with endometriosis and healthy controls, and to explore how the density of these nerve fibers and hormone levels correlate with the severity of symptoms experienced by the women.

Study Design: In this case-control study, 76 women with endometriosis and 24 healthy controls were included. The patient group was divided into two subgroups: those with and without hormonal treatments. Endometrial biopsies were taken and stained to detect PGP 9.5, a nerve fiber marker. Blood samples were collected for hormone analysis. Pain symptom severity was measured using VAS and EHP30.

Results: Women with endometriosis had a higher density of endometrial nerve fibers than healthy controls (median [range]: 2.0 [2.0–4.0] vs. 1.0 [0.0–1.0] fibers/mm², P < 0.001). This increased density was associated with more severe pain (β = 0.130 [95 % CI: 0.019, 0.240], P = 0.02). Women with endometriosis, regardless of hormone treatment, had a higher density of endometrial nerve fibers (3.0 [2.0–4.0] and 2.0 [1.0–4.0] fibers/mm², respectively) compared with healthy controls (1.0 [0.0-u1.0] fibers/mm², both P < 0.001). The density was not significantly different between those receiving and not receiving hormone treatment. The allopregnanolone/progesterone ratio was greater in women with endometriosis not receiving hormone treatment (0.002 [0.001–0.004]) than in healthy controls (0.001 [0.000–0.005]) and women receiving hormone treatment (0.001 [0.000–0.006], P = 0.02 and 0.001, respectively). A greater allopregnanolone/progesterone ratio was associated with more severe pain (β = 20.662 [95 % CI: 0.202, 41.121], P = 0.048), but hormone levels (estrogen, progesterone, and allopregnanolone) were not associated with endometrial nerve fiber density.

Conclusion: Women with endometriosis have a higher nerve fiber density in the endometrium, linked to more severe pain, regardless of hormone treatment. Increased progesterone metabolism to allopregnanolone may be a target for managing endometriosis pain.

Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.

Introduction: The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABAA) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABAA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABAA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relationship between GABAA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABAA receptor, in the participating women.

Material and methods: 15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom-free, control women, aged 18–40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection.

Results: Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABAA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels.

Conclusions: Women with painful endometriosis show altered GABAA receptor function, depicted as a muted response to an exogenous GABAA receptor agonist.

Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01–3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1–3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP’s negative effects on LoR and learning in the MWM.

Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the estrus cycle phase containing moderately increased levels of positive GABA-A receptor-modulating steroids (steroid-PAM), especially allopregnanolone (ALLO), and if the adverse behavior can be antagonized. The electrophysiology studies in this paper show that isoallopregnanolone (ISO) is a GABA-A-modulating steroid antagonist (GAMSA), meaning that ISO can antagonize the agonistic effects of positive GABA-A receptor-modulating steroids in both α1β2γ2L and α4β3δ GABA-A receptor subtypes. In this study, we also investigated whether ISO could antagonize the estrus cycle-dependent aggressive behaviors in female Wistar rats using a resident–intruder test. Our results confirmed previous reports of estrus cycle-dependent behaviors in that 42% of the tested rats showed higher levels of irritability/aggression at diestrus compared to those at estrus. Furthermore, we found that, during the treatment with ISO, the aggressive behavior at diestrus was alleviated to a level comparable to that of estrus. We noticed an 89% reduction in the increase in aggressive behavior at diestrus compared to that at estrus. Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior.