Molecular Mechanisms of Menstrual Cycle–Related Suicide Risk: A Selective Review of Promising Candidate Systems

Abstract

Females of reproductive age experience more suicidal ideation, suicide attempts, and psychiatric hospitalizations than their male counterparts—with high risk during periods of hormonal transitions (e.g., puberty, the menstrual cycle, and pregnancy), suggesting a role for cyclical ovarian hormone fluctuations in suicide risk. This role is supported by cross-sectional and longitudinal studies showing that the menstrual cycle can trigger or exacerbate suicidal symptoms in susceptible individuals, particularly during the luteal and perimenstrual phases. However, brain-based mechanisms linking hormonal dynamics to suicidality remain underexplored. In hormone-sensitive individuals, normal fluctuations in estradiol (E2), progesterone (P4), and the neuroactive steroid allopregnanolone (ALLO) may disrupt the molecular mechanisms of mood regulation, cognitive processing, and behavioral control. This selective review synthesizes evidence across 6 promising molecular systems—serotonergic, GABAergic (gamma-aminobutyric acidergic), dopaminergic, neurotrophic, lipid, and DHEA(S) (dehydroepiandrosterone/dehydroepiandrosterone sulfate)—that are modulated by E2, P4, or ALLO and implicated in suicide pathophysiology. Drawing on neuroimaging, genetic, pharmacologic, and hormone manipulation studies, we describe potential mechanisms of cyclical suicide risk and their interactions with genetic and epigenetic vulnerability. Framed within the Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle model, we outline the following research priorities: high-frequency within-person designs, hormone-informed neuroimaging, and personalized modeling approaches to identify modifiable, temporally precise mechanisms. Integrating menstrual cycle dynamics into suicide neuroscience may advance precision prevention for a large and underserved population.

Despite decades of cross-sectional research identifying molecular correlates of suicide (1), we have made limited progress toward predicting when an individual will experience acute risk. Striking sex differences in suicidal behavior could offer a clue: females of reproductive age experience more suicidal ideation (SI), suicide attempts (SAs), and psychiatric hospitalizations than their male counterparts—with high risk observed during times of reproductive hormone flux such as puberty (2), the menstrual cycle (3), and pregnancy (4). Indeed, the preponderance of evidence finds the greatest risk of attempt during the 2 weeks surrounding menstrual onset (3), and longitudinal studies have demonstrated parallel fluctuations in SI (5,6).

The menstrual cycle, regulated by the hypothalamic-pituitary-gonadal axis, involves rising estradiol (E2) during the follicular phase, peak E2 near ovulation, and subsequent luteal-phase production of E2 and progesterone (P4). Without fertilization, E2 and P4 decline, triggering menstruation. These hormones and their metabolites, particularly neuroactive steroids (NASs) such as allopregnanolone (ALLO), are both reproductive and neuroactive, impacting neurosteroid, neurotransmitter, and neurotrophic mechanisms relevant to neuropsychiatric and suicide risk.

Individuals differ widely in how their mood, thoughts, and behaviors respond to hormonal changes across the cycle. Although many individuals experience minimal changes, others exhibit moderate-to-severe cyclical affective or behavioral symptoms (7). Clinically recognized manifestations of psychiatric symptom cyclicity include premenstrual dysphoric disorder (PMDD), characterized by pronounced luteal symptoms resolving postmenses, and pre- or perimenstrual exacerbation (PME), marked by worsening chronic psychiatric symptoms in the luteal phase or around menses. PMDD affects approximately 5.5% of reproductive-age females, with high lifetime rates of SI (72%) and SA (34%) (8). PME is more common, occurring in approximately 58% of those with depression, and has similarly been linked to suicidality (6,9).

Importantly, hormonal profiles in these cyclical disorders are normal, suggesting that vulnerability arises from brain-level sensitivity to hormone change rather than endocrine dysfunction (10). The Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework proposes 2 key triggers of psychiatric symptoms and suicide risk. First, E2 withdrawal—through acute drops or deficits—contributes to both PME of depression and increased suicidality (11,12). Second, periovulatory surges in ALLO, driven primarily by P4, trigger symptoms in individuals with luteally confined PMDD (13). These hormonal triggers shaped our perspectives regarding the mechanisms relevant to cyclical suicidality.

In this selective review, we explore 6 systems chosen for their intersecting links to suicide (especially attempts, deaths) and modulation by the cycle (serotonergic, GABAergic [gamma-aminobutyric acidergic], dopaminergic, neurotrophic, lipid, and DHEA(S) (dehydroepiandrosterone/dehydroepiandrosterone sulfate) (Figure 1). Our goal was to highlight evidence within systems that have been of high interest while bringing new perspectives to those that remain underexplored. However, this list is not exhaustive, and others are of interest although not included here (e.g., oxytocin, glutamatergic, and adrenergic). Although stress and trauma-related systems seem to play a role in chronic risk, they are excluded due to their inconsistent links to psychiatric symptom cyclicity and coverage elsewhere (14–17). Each section focuses on reproductive-age female-specific findings when possible; however, the historic exclusion of females in suicide research is an important limitation (18). Furthermore, we include both preclinical and clinical findings but acknowledge that hormone dynamics differ substantially between species (e.g., ~4-day rodent estrous cycle vs. ~28-day human menstrual cycle) (19) and should be interpreted cautiously. For each system, we summarize associations with suicidality and hormones and discuss translational potential as a mechanism of cyclical suicidality.

Figure 1.

Molecular mechanisms of menstrual cycle–related affective and suicide risk: a selective review of promising candidate systems. Candidate molecular systems, steroid triggers, and overlapping evidence in clinical and preclinical models of hormone sensitivity and suicide. The dashed suicide risk line represents the mean suicidality change pattern observed in Ross et al. (6). (Figure created in BioRender.) 5HT_1A, serotonin receptor 1A; 5HT_2A, serotonin receptor 2A; 5-HTTLPR, serotonin-transporter-linked promoter region; 5-HTT, serotonin transporter; ALLO, allopregnanolone; ApoB, apolipoprotein B; BDNF, brain-derived neurotrophic factor; COMT^Met, COMT Met-carrier; COMT^Val, COMT Val-carrier; CSF, cerebrospinal fluid; D₁, dopamine receptor 1; D₂, dopamine receptor 2; DA, dopamine; DAT, dopamine transporter; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DOPAC, 3,4-dihydroxyphenylacetic acid; E2, estradiol; EBR, eye blink rate; GABA, gamma-aminobutyric acid; GABA_AR, GABA_A receptor; GnRHa, gonadotropin-releasing hormone agonist; HDL-C, high-density lipoprotein cholesterol; HVA, homovanillic acid; IV, intravenous; LDL-C, low-density lipoprotein cholesterol; LIPA, lysosomal acid lipase; NSSI, nonsuicidal self-injury; P4, progesterone; PCSK9, proprotein convertase subtilisin/kexin type 9; PMDD, premenstrual dysphoric disorder; PPD, postpartum depression; SNP, single nucleotide polymorphism; TC, total cholesterol; TG, triglyceride.

SEROTONIN

Serotonin (5-HT), synthesized in the brainstem raphe nuclei, regulates mood, cognition, and behavior through wide-spread projections (20). Signaling depends on coordinated synthesis, receptor binding, and reuptake via the 5-HT transporter (5-HTT), contributing to affective states and their regulation (21).

5-HT→Suicidality

Links between the serotonergic system and suicidality are complex, with research revealing various risk pathways (1) and consistent but underdefined sex differences. Positron emission tomography (PET) studies indicate reduced 5-HTT expression in individuals with a history of SA (22). Supporting evidence includes positive correlations between 5-HT_1A binding and stress in individuals with a history of SA (23) and higher 5-HT_1A binding in the raphe associated with higher-lethality SAs (24). Postmortem studies converge, reporting higher 5-HT_1A and 5-HT_2A binding and reduced 5-HTT binding in suicide decedents compared with controls, with females exhibiting lower 5-HTT (25) and higher 5-HT_1A (26). Levels of 5HT_2A receptor, protein, and messenger RNA (mRNA) are higher in the prefrontal cortex (PFC) and hippocampus of adolescents who died by suicide (27). Depletion of tryptophan, a 5-HT precursor, triggers depressive symptoms in individuals with histories of suicidal behavior, particularly females and those with recurrent depression (possibly driven by hormone-sensitive cyclical episodes) (28).

Genetic factors may play a role. The short (S) allele of the 5-HTTLPR polymorphism is associated with lower 5-HTT expression and potentially higher synaptic 5-HT, possibly leading to receptor dysregulation and increased suicidality. A meta-analysis confirmed associations between specific polymorphisms, such as rs6295 of the HTR1A gene, and suicidal behavior (29). Furthermore, state-level biomarker studies have shown increased SLC6A4 expression (encoding greater 5-HTT) predicting high suicidal states, especially in females, suggesting that increased 5-HT reuptake may be a marker for acute risk (30,31). The intersection of these findings with hormones and hormone-sensitive populations may be critical for understanding sex differences in pathways to suicidality.

Hormones→5-HT

Several lines of evidence implicate the serotonergic system in symptom cyclicity. Studies examining 5-HTT binding across the cycle are mixed; one PET study (N = 8) found no follicularluteal differences (32), but a better-powered study (N = 63) using a gonadotropin-releasing hormone agonist (GnRHa) to pharmacologically induce hormone withdrawal through ovarian suppression triggered increased cortical 5-HTT binding and subclinical depression, both linked to degree of E2 withdrawal (33). In individuals with PMDD, midbrain 5-HTT binding is elevated compared with control participants (34), with premenstrual (low E2) increases contrasting with the periovulatory phase (high E2), a pattern opposite to that seen in control participants and correlating with depression. These findings suggest increased 5-HTT availability during hormone withdrawal in hormone-sensitive individuals. Additionally, a single-point PET study in naturally cycling individuals found that lower serum ALLO was associated with higher prefrontal 5-HTT binding (35). However, conclusions are limited due to the absence of within-person measurements or phase-specific scanning. Furthermore, a study (N = 5) of individuals with PMDD found that, unlike control participants who showed increased luteal dorsal raphe 5-HT_1A binding, individuals with PMDD exhibited no cycle-related 5-HT_1A changes (36), indicating blunted receptor plasticity. Finally, E2 (37) and E2+P4 (38) treatment increase 5-HT_2A binding in postmenopausal women, but replication in reproductive-age individuals is needed. Together, findings in PMDD suggest state-level (5-HTT) or trait-level (5-HT_1A) differences in serotonergic responsiveness to the cycle. Larger, well-powered studies with high-frequency scanning are critical to disentangle the timing of these dynamic changes.

Metabolomic studies support these findings, showing luteal phase decreases in neurotransmitter precursors tryptophan, glutamine, and tyrosine in control participants (39). In hormone-sensitive individuals, failure to adequately compensate for this drop may contribute to reduced 5-HT synthesis. Supporting this, individuals with PMDD have significantly lower luteal whole-blood 5-HT (40), and their response to both intravenous and oral tryptophan loading (normally boosting 5-HT) is blunted luteally compared with the follicular phase (41,42). This is mechanistically consistent with trials demonstrating rapid benefits of selective serotonin reuptake inhibitors (SSRIs) in PMDD (43) and experiments demonstrating the return of symptoms with metergoline (a 5-HT receptor [5-HTR] antagonist) in those with prior symptom relief (44).

Genetic factors may compound vulnerability: individuals with PMDD carrying the 5-HTTLPR S-allele show greater background affective symptoms (45). Moreover, the G/G homozygous HTR1A genotype (rs6295) predicts premenstrual working memory deficits in PMDD (46), suggesting hormonally modulated cognition via 5-HTRs. Although no studies have linked 5-HTTLPR to cyclical suicidality, S-allele carriers experiencing steeper E2 drops have greater risk of postpartum depression (47).

Summary

The 5-HT system may mediate cyclical affective and suicide risk linked to ALLO surge and E2 withdrawal sensitivities delineated in the DASH-MC. E2, P4, and ALLO influence 5-HTT activity, 5-HT_1A/2AR binding, and 5-HT synthesis, particularly during hormone flux. These effects are amplified in PMDD, including premenstrual increases in 5-HTT binding and blunted tryptophan responses. Further research on 5-HTRs in reproductive-age females and on genetic variants (5-HTTLPR S-allele, HTR1A rs6295) alongside NAS and state-dependent biomarkers (e.g., SLC6A4 expression) will improve personalized risk stratification.

GAMMA-AMINOBUTYRIC ACID

GABA is the brain’s principal inhibitory neurotransmitter and is critical for regulating affect and stress responsivity. The GABA_A receptor (GABA_AR), a pentameric chloride channel, is modulated by NASs such as ALLO, a 5α-reduced metabolite of P4. GABA_AR subunit composition—the stoichiometry of α, β, γ, and/or δ subunits—influences its responsivity to modulators (48).

Both P4 and E2 increase central NAS levels, which fluctuate across the cycle, particularly during the luteal surge and perimenstrual withdrawal. These fluctuations influence GABA_AR composition and related inhibition in brain circuits that regulate emotion, and in hormone-sensitive individuals, even physiologically typical changes in NAS may destabilize GABAergic tone. Although lower ALLO levels and ALLO:P4 ratios have been observed in individuals with MDD, posttraumatic stress disorder, and anorexia nervosa and in suicide decedents (49), those with luteally confined PMDD show no peripheral NAS deficits under experimental conditions (50,51). As a P4 metabolite, peripheral ALLO follows normal luteal patterns, and the body of evidence—especially experimental—does not implicate aberrant NAS levels or trajectories as the cause of cyclical symptoms in hormone-sensitive individuals. Instead, they exhibit acute affective symptoms in response to normal luteal ALLO increases, symptoms preventable by blocking ALLO synthesis through 5α-reductase inhibition (52). This paradoxical response suggests a core role for altered GABA_AR composition and sensitivity rather than absolute NAS levels in mediating vulnerability to cyclical psychiatric symptoms and suicidality [note: since these frequently co-occur, NAS deficits and change sensitivity may also co-occur (53)]. Thus, this section focuses on aberrant NAS-mediated GABA_AR plasticity (and associated functional differences of ALLO at GABA_AR) as a plausible molecular mechanism linking the menstrual cycle to suicide risk in susceptible individuals.

GABA_AR→Suicidality

Several lines of evidence suggest that differences in GABA_AR function may contribute to suicide risk. Postmortem studies reveal altered expression of GABA_AR subunits in suicide decedents, including increased prefrontal α4 and δ subunit expression in females (54) and less coordinated gene expression observed between subunits in the cortex, hippocampus, and amygdala (55). Epigenetic factors may contribute; hypermethylation of the α1 subunit promoter and broader GABA-related methylation differences have been found in suicide decedents with and without MDD (56). Additionally, polymorphisms in genes encoding α4, δ, and γ2 subunits have been associated with suicide risk (57). Functional imaging supports these findings: a ¹H-MRS study found reduced anterior cingulate GABA levels in females with suicidal behavior (58). Taken together, both genetic/epigenetic alterations and downstream neurotransmitter dysregulation in GABAergic systems seem relevant to suicide pathophysiology.

Hormones→GABA_AR

Menstrual cycle-driven shifts in E2 and P4 likely impact GABAergic signaling through changes in GABA_AR subunit composition (59). ALLO potentiates GABA_AR activity, but in hormone-sensitive individuals, luteal ALLO surges paradoxically trigger symptoms of anxiety, impulsivity, and aggression (60), likely due to dynamic GABA_AR plasticity (60–62). These effects seem specific to hormonal surges because withdrawal of E2 and P4 mid-luteally does not worsen symptoms in individuals with luteally confined PMDD (63), whereas pharmacological blockade of P4-to-ALLO conversion reduces symptoms (52). Additionally, isoallopregnanolone, a 3β-isomer of ALLO that antagonizes the GABA_AR, shows efficacy in reducing luteally confined PMDD symptoms (64,65).

Preclinical studies have demonstrated that α and δ GABA_AR subunits are particularly NAS sensitive. Acute increases and decreases in P4 or ALLO, similar to those observed across the menstrual cycle, precipitate increases in δ (66) and α4 (67,68) mRNA and protein. Notably, increases in α4 subunit expression (the subunit found to increase uniquely in female suicide victims) correlate with anxiety behavior in rodent studies (68,69). Additionally, ALLO withdrawal produces anxiety-like behaviors in mice only in GABA_ARs with a δ subunit (70).

Translational proxies in humans support this model. In PMDD, δ and β2 subunit mRNA levels in peripheral mononuclear cells were lower in the luteal versus follicular phase, and lower δ subunit corresponded with greater luteal amygdala activation (71). Peripheral mRNA expression of the γ2 subunit seems downregulated during pregnancy compared with the nonpregnant state (72), translating animal studies demonstrating regulation of γ2 by P4 (73). However, peripheral findings may not reflect central levels. Cycle phase–specific differences in GABAergic tone are also reflected physiologically; saccadic eye velocity is altered in individuals with luteal-onset affective symptoms (74), and luteal-phase anxiety-potentiated startle is elevated in PMDD (75).

Summary

Fluctuations in E2 and P4 across the cycle alter NAS concentrations, particularly ALLO, which then modulate GABA_AR function. For some, particularly those with ALLO surge sensitivity as hypothesized in the DASH-MC framework, typical hormonal changes may destabilize GABAergic tone via receptor-level plasticity rather than NAS deficiency. GABA_AR subunit expression changes, especially α4 and δ, seem to sensitize the brain to NAS fluctuations and are mirrored in suicide-relevant human postmortem and genetic data. Together, this suggests that hormone-driven GABA_AR plasticity may link the cycle to increased suicide risk in susceptible individuals.

DOPAMINE

Dopamine (DA) is a neurotransmitter that orchestrates motivation, reward, motor control, and executive cognitive functions. It acts through D₁ to D₅ receptors (D₁-like: D₁, D₅; D₂-like: D₂–D₄), with D₁-like receptors facilitating excitatory signaling in corticostriatal circuits, enhancing working memory, and amplifying reward-associated learning and motivation (76), whereas D₂-like receptors mediate autofeedback inhibition, effectively lessening DA neuron excitability, limiting DA release, and reducing available DA by increasing dopamine transporter (DAT) activity (77).

Baseline DA availability is shaped by polymorphisms in the catechol-O-methyltransferase (COMT) gene, which encodes the enzyme that degrades DA. The common Val158Met variant alters enzyme activity as follows: Val/Val carriers have high COMT activity/lower DA, Met/Met carriers have low COMT activity/higher DA, and Val/Met individuals fall in between. COMT Val158Met has been associated with sex-specific differences in cognition and working memory (78).

DA→Suicidality

DA dysfunction is implicated in suicidality (79). Reduced DA turnover is found in SA as evidenced by lower homovanillic acid (HVA) in urine (80) and cerebrospinal fluid (CSF) (79), reduced postmortem brain 3,4-dihydroxyphenylacetic acid (DOPAC) (81), and blunted response to DA agonists (82). Receptor and transporter differences have been observed, including altered D₁/D₂ binding (83), lower DAT availability in the basal ganglia (84), and DRD2 (85) and DAT1 (86) associations with suicidality. DA-related traits such as executive dysfunction (both hyper- and hypocontrol) are common in attempters (87), but DA’s role in suicide remains underexplored. Notably, a meta-analysis found higher suicide risk in female COMT Met-allele carriers (higher baseline prefrontal DA) (88).

Hormones→DA

E2 modulates DA activity primarily in females, due in part to sex-specific expression and localization of E2 receptors within DA pathways (89,90). In female rodents, striatal DA concentrations differ in an estrous cycle phase-dependent manner (91), and application of E2 increases DA and DOPAC synthesis (92). In humans, E2 fluctuations across the cycle correspond with DA-linked symptoms—including impaired working memory (93,94), inattention, impulsivity (95), and alcohol use (96,97)—particularly in those with underlying vulnerability to the same symptoms. DA follows an inverted U-shaped curve; both low and high levels impair PFC-mediated executive function. E2 and P4 can modulate this balance through their regulation of COMT gene transcription because both estrogen-response elements (EREs) and P4-response elements (PREs) are present on the COMT promoter (98). E2 lowers COMT activity and increases DA availability (99); thus, E2 withdrawal can tip DA below optimal levels, thereby impairing executive functioning (100). In naturally cycling individuals, those with lower baseline DA (e.g., COMT Val/Val) show worse working memory during low-E2 phases, while higher-DA individuals (Met carriers) show preserved or improved function (93,94). Notably, in the most direct test of this mechanism, naturally cycling females with SI exhibited perimenstrual worsening in working memory and verbal fluency, effects that were reversed by transdermal E2 administration (0.1 mg/day vs. placebo) (100) in concert with reduced suicidality (12). These findings suggest that E2 withdrawal may disrupt DA-regulated cognitive control with implications for cyclical suicidality. Supporting this, individuals with PMDD show reduced CSF HVA/5-HIAA ratios during symptomatic phases, which negatively correlate with serum E2 and P4 (101), indicating reduced DA relative to 5-HT turnover in the context of E2 withdrawal. Although PET studies report no cyclical differences in D₂ receptor availability, genetic or epigenetic variation in COMT or DRD2 may obscure hormone-dependent effects (102).

P4 seems to alter E2 regulation of impulsivity in animals (103) and humans (104). Individual differences again likely play a role. In one study, eye blink rate (EBR)—a noninvasive proxy for central DA tone (105)—interacted with P4 to predict cognitive shifting; during the high-P4 luteal phase, those with low baseline EBR (lower DA) showed improved cognition, while those with high EBR (higher DA) declined (106). Notably, EBR itself does not seem to vary across the cycle in control participants (107).

Summary

Fluctuations in E2 and P4 alter DA activity and metabolism, and genetic differences in DA are linked to changes in cognitive functions across the cycle. To date, these changes seem most relevant to perimenstrual E2 withdrawal sensitivity; however, emerging evidence implicates DA pathways in luteal sensitivity to P4 (i.e., ALLO surges). Despite strong biological rationale and promising initial clinical studies, DA mechanisms remain largely untested in cyclical psychiatric symptoms or suicidality. To test causality, future studies must directly manipulate DA through stimulant administration, D₂/D₃ receptor agonists or antagonists, or pharmacologic functional magnetic resonance imaging (fMRI). These studies must consider how individual differences in DA biomarkers (e.g., EBR, HVA, COMT genotype) interact with dynamic hormone changes to produce acute perimenstrual suicide risk.

BRAIN-DERIVED NEUROTROPHIC FACTOR

Brain-derived neurotrophic factor (BDNF) is a central regulator of synaptic remodeling, neuronal survival, and neuroplasticity, primarily through the TrkB receptor. It is highly expressed in brain regions critical for affect regulation, such as the hippocampus, PFC, and amygdala, which are also rich in steroid hormone receptors.

BDNF→Suicidality

Suicidality has frequently been linked to impaired BDNF signaling. Functionally, the Met allele of the common Val66Met polymorphism impairs intracellular trafficking and activity-dependent BDNF release, reducing neural adaptability under stress (108). Consistent with this mechanism, the Met allele of the BDNF Val66Met polymorphism is disproportionately represented among female suicide decedents (109), and this variant—along with polymorphisms in the TrkB receptor gene NTRK2—are associated with SA (110–112). Additionally, epigenetic suppression of BDNF expression through promoter methylation is linked to SI, SA, and poor antidepressant response (113). At the protein level, meta-analyses have shown lower peripheral plasma BDNF concentrations among individuals with depression and prior SA (114,115), findings supported by postmortem studies demonstrating reduced BDNF expression in the hippocampus and PFC (116,117). Taken together, this evidence suggests that reduced BDNF signaling, whether from genetic, epigenetic, or downstream protein changes, may reduce neuroplasticity and impair adaptability to stressful situations, possibly increasing vulnerability to suicidal behavior.

Hormones→BDNF

BDNF expression is tightly regulated by ovarian hormones across the menstrual cycle. E2 upregulates BDNF transcription through EREs (118,119), and BDNF tracks closely with E2, with a late-follicular and mid-luteal pattern and a drop-off during low-E2 states such as menstruation, amenorrhea, and menopause (120) that can be partially reversed with E2 therapy (121). P4 and ALLO may also enhance BDNF expression, although this effect is less consistent and often dependent on E2 priming (122,123).

In PMDD, cyclical BDNF regulation is disrupted, with paradoxical elevations during the symptomatic luteal phase (124–126). This may reflect either a compensatory response to symptom-related stress (125) or a maladaptive pattern that contributes to an exaggerated perimenstrual BDNF drop. Furthermore, BDNF regulates the expression of GABA_AR subunits—particularly increasing PMDD-relevant α4 and δ subunits—which could further contribute to a steroid surge-sensitive phenotype by impairing tonic inhibition and heightening excitability (see GABA_AR) (127,128).

In cycling transdiagnostic outpatients recruited for SI, we observed dimensional perimenstrual worsening of both SI and working memory under placebo, which were reversed by E2 but not P4 administration (6,12,100). Given that working memory depends on the E2- and BDNF-sensitive dorsolateral PFC (129)—and is itself a key cognitive domain implicated in suicidality (130)—one intriguing possibility is that this reflects a hormone-sensitive BDNF mechanism, although this has not yet been directly tested.

Individual differences in BDNF signaling may mediate or amplify risk (131). In PMDD, the BDNF-lowering Val66Met polymorphism is associated with reduced frontocingulate activation during the luteal phase (132), indicating disrupted top-down regulation despite elevated BDNF levels. In rodent models, Met carriers show depression-like behavior following E2 reintroduction, mimicking the surge sensitivity seen in PMDD (13,133). Epigenetic mechanisms also play a role; females with borderline personality disorder, a group with high hormone sensitivity and suicide risk, show increased BDNF promoter methylation, which correlates with suicidal behavior severity (134,135). However, these data are derived from peripheral blood and may not fully reflect methylation status in the brain.

Summary

BDNF fluctuates across the menstrual cycle and interacts with mechanisms of hormone sensitivity. Limited available evidence points to the possible relevance of BDNF pathways to both perimenstrual E2 withdrawal and luteal ALLO surge sensitivities. Particularly, it seems plausible that BDNF serves as a potential mediator of serotonergic and GABAergic mechanisms described throughout. Further genetic and epigenetic research connecting cyclical suicidality and ovarian hormones is warranted.

LIPIDS

Lipids play essential roles in neural homeostasis (136). As key components of cell membranes, circulating lipids—including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TGs)—support membrane stability, synaptic signaling, blood-brain barrier integrity, inflammatory regulation, and neuronal metabolism. Cholesterol also serves as the precursor for all steroids, while polyunsaturated fatty acids (PUFAs) modulate neuroinflammation and synaptic plasticity as constituents of cell membranes.

Lipids→Suicidality

Low cholesterol has been linked to suicide risk since its identification as a side effect of lipid-lowering medications (137), with meta-analyses confirming lower serum TC, LDL-C, HDL-C, and TGs in individuals with SAs (138,139). Postmortem studies have shown reduced cholesterol in the PFC of suicide decedents (140), while molecular data suggest that cholesterol depletion or accelerated metabolism—through altered lipid gene expression (e.g., SNAP25), elevated LIPA, and oxysterols—may impair membrane integrity (141,142). Low cholesterol and PUFA levels may disrupt lipid rafts, thereby compromising 5-HT transporter/receptor function and reducing 5-HT signaling (143,144), consistent with lower CSF 5-HIAA in attempters (145) and PUFA deficits predicting suicidality (146).

Hormones→Lipids

Female-specific findings suggest a more complex relationship. Some studies have reported that high TC and TG are linked to suicidality and female depression (147,148), although these samples often include postmenopausal individuals. Lipid profiles fluctuate across the cycle; HDL-C and TGs rise during high P4 in the luteal phase, while non-HDL-C, apolipoprotein B, and serum PCSK9, which regulates LDL receptors, peak when E2 is low, correlating with higher TC, LDL-C, and TGs (149,150). The effects of P4 on lipids remain unclear, with mixed findings on whether it opposes or has neutral interactions with E2 (151). Individuals with PMDD show higher late-luteal cholesterol than control participants (152), although changes in appetite and diet may contribute. Cyclical lipid changes may alter lipid raft structure and modulate neurotransmission through hormone-sensitive receptors such as 5-HTRs (153).

Summary

Longitudinal studies of lipids and suicidality across the cycle are needed to clarify their relationship. Although low cholesterol and other lipids and cholesterol turnover are generally linked to suicidality, some studies have reported that high lipid levels were associated with female suicidality. Lipid levels may fluctuate across the cycle (e.g., higher during low E2), but it remains unclear whether these patterns intersect with hormone sensitivity.

DHEA(S)

DHEA and its sulfate ester [DHEAS] are adrenal neurosteroids and precursors to E2 and testosterone. Beyond their role in steroidogenesis, DHEA(S) exert direct neuromodulatory effects, antagonizing GABA_ARs (154), enhancing serotonergic tone (155), buffering glucocorticoid impact (156), and reducing inflammation (157). These actions confer neuroprotective and cognitive benefits (158).

DHEA(S)→Suicidality

Most studies report lower DHEA(S) levels in individuals with suicidal behavior (159,160), with DHEAS more consistently implicated. Elevated cortisol/DHEAS ratios, suggesting hypothalamic-pituitary-adrenal axis dominance over NAS production, have been linked to nonsuicidal self-injury and emotional dysregulation (161). However, contradictory findings exist (162), possibly due to differences in sex, diagnosis, or hormonal state.

Hormones→DHEA(S)

DHEA remains relatively stable across the cycle (163,164), whereas DHEAS decreases mid-luteally (163), possibly due to fluctuating sulfotransferase activity. P4 and ALLO may upregulate DHEA(S) in healthy individuals, whereas E2’s effects seem more variable (50).

In hormone-sensitive groups, DHEA(S) regulation seems disrupted. In PMDD, DHEA and DHEAS levels paradoxically decline following both E2 and P4 administration rather than increasing or remaining stable as has been observed in the control group (50). This may reflect altered steroidogenic enzyme function or impaired sulfation, leading to reduced DHEAS formation and faster NAS clearance. DHEA levels also correlate with GABA_A δ subunit expression in peripheral immune cells (165), suggesting that DHEA influences GABA_AR sensitivity to luteal ALLO surges that drive luteally confined PMDD (52). In perimenopausal depression, where symptoms can be triggered by E2 withdrawal (166) as they can in perimenstrual suicidality (11,12), mood sensitivity to E2 withdrawal is associated with elevated expression of CYP7B1, a DHEA-catabolizing enzyme, and reduced circulating DHEA (167). These findings suggest that deficits in DHEA may lead to vulnerability during hormone flux, either through low precursor reserves or NAS action, and that impaired DHEA availability could underlie cyclical suicide risk related to either E2 withdrawal or P4/ALLO surges.

Summary

Together, findings suggest that in individuals sensitive to hormonal transitions, blunted or dysregulated DHEA(S) metabolism may impair GABAergic and serotonergic modulation during both luteal ALLO surges and experimental E2 withdrawal (in perimenopause), potentially contributing to the cyclical emergence of suicidal symptoms in hormone-sensitive individuals.

CONCLUSIONS

The menstrual cycle offers a temporally precise, causally constrained framework for tracing the neurobiology of acute suicidality in PMDD and PME. Among those with hormone-sensitive suicidality, some may be sensitive to luteal ALLO surges, others to perimenstrual E2 withdrawal, and others to some alternative or combination as outlined in the DASH-MC framework (13). This variability reflects a broader insight that suicidality is not a unitary phenomenon. Individuals may reach similar suicidal outcomes through distinct neurobehavioral mechanisms (168,169).

A complex network of interdependent molecular pathways may underlie cyclical risk of suicidal thoughts and behaviors, with critical systems varying across specific individuals and phenotypes. For individuals sensitive to steroid surges, the luteal ALLO rise may destabilize GABA_AR function through subunit expression alteration further modulated by cyclical changes in BDNF and/or DHEA. Individuals sensitive to perimenstrual E2 withdrawal may experience reduced serotonergic tone, impaired dopaminergic modulation, and downregulated neurotrophic support. These differences may underlie observed noncanonical rapid effects of SSRIs. The systems described interact in many ways: 5-HT_2AR/5-HT_2CRs regulate DA transmission (170), and lipids can change receptor function by altering membrane integrity, such as with the D₂ receptor (171). SSRIs can both increase BDNF expression (172) and exert region-specific effects across monoaminergic circuits depending on receptor architecture (173,174). Genetic and enzymatic variability (e.g., COMT Val158Met, BDNF Val66Met) may moderate individual responses to hormonal changes. These findings argue against a single hormone-based model in favor of personalized, dimensional network models of risk among those with prospectively documented cyclical suicidality.

Despite its potential, menstrual neurobiology has remained largely disconnected from suicide neuroscience. Most suicide neuroimaging studies have relied on between-subject designs and exclude hormone-sensitive individuals, while cycle studies often focus on healthy control participants and rely on sparse hormone sampling. To advance, we need high-frequency, within-subject studies to capture the dynamic neurobiology of cyclical risk and how it varies across individuals. Studies should oversample hormone sensitivity, measure daily symptoms and hormones, and use multimodal imaging during acute hormonal flux. Experimental hormone manipulation studies incorporating PET or fMRI are essential to identifying causal mechanisms. Development of radioligands, particularly for GABA_AR subunits, estrogen receptor beta, and dopaminergic targets, is needed. Animal studies that capture sources of individual differences in sensitivity to the same hormonal trigger are also absent and critically needed.

Innovative analytic approaches are needed: idiographic modeling (168), latent subgroup analysis, and machine learning offer tools for identifying individualized risk profiles. When integrated with person-level genetic, molecular, and neural data, these methods could uncover biologically meaningful subtypes and inform personalized medicine (e.g., luteal SSRIs vs. perimenstrual E2). Novel therapeutics also show promise: mifepristone (glucocorticoid and P4 receptor antagonist) and E2 were identified as reversing suicidality-associated gene expression profiles (175).

Although menstrual cycle working subgroups affiliated with larger consortia have emerged for neuroimaging (ENIGMA [Enhancing Neuro Imaging Genetics through Meta Analysis]) or are planned (Ann S. Bowers Women’s Brain Health Initiative), there is a lack of professional organizations dedicated to menstrual cycle mental health research—despite it having comparable population-level impact as perinatal and perimenopausal transitions, which benefit from established international organizations (e.g., the International Marcé Society for Perinatal Mental Health, the Menopause Society [previously the North American Menopause Society]). Building biobanks, training pipelines, clinical science societies, and standardized cycle methods is essential to accelerate progress. If this challenge is met, there is substantial potential to uncover modifiable, time-locked brain mechanisms of suicide risk, offering a path toward prevention in a large and underserved population.