Estrogen & Progesterone for Suicidal Thoughts: What the Research Says

randomized-controlled-trial PMID: 37611527

Quick Summary: Researchers studied how hormone therapy (estrogen and progesterone) affects brain chemicals and inflammation in women with suicidal thoughts. They found that the therapy changed certain brain chemicals linked to mood, but the study didn't directly test pregnenolone.

What The Research Found

This study looked at how hormone therapy (estrogen and progesterone) affects brain chemicals called neuroactive steroids (NAS) and inflammation in women with a history of suicidal thoughts. The therapy seemed to boost some NAS related to progesterone, while other NAS decreased. Inflammation markers didn't change with the menstrual cycle but were linked to mood issues.

Study Details

Who was studied: 26 women with mental health conditions and suicidal thoughts. They all had regular menstrual cycles.

How long: The study looked at blood samples taken at different times during their menstrual cycles.

What they took: Some women received estrogen and progesterone hormone therapy, while others received a placebo (a "dummy" treatment).

What This Means For You

This research suggests that hormone changes can affect brain chemicals related to mood. If you experience worsening mood around your period, talking to your doctor about hormone therapy might be helpful. However, this study didn't test pregnenolone directly, so it doesn't tell us if pregnenolone supplements would help.

Important Note: This study focused on hormone therapy (estrogen and progesterone), not pregnenolone supplements.

Study Limitations

Small Study: Only a small number of people were involved, so the results might not apply to everyone.

Short-Term: The study only looked at a short period of time.

Specific Group: The study focused on women with mental health conditions and suicidal thoughts.

No Pregnenolone: The study did not directly test pregnenolone supplementation.

More Research Needed: The findings are preliminary and need to be confirmed by larger studies.

Key Findings

The study found that exogenous perimenstrual administration of estradiol and progesterone (EP) altered neuroactive steroid (NAS) pathways linked to pregnenolone, a precursor to both progesterone and androstane steroids. P4-derived NAS (e.g., 3α,5α-THP, 3α,5β-THP, 3α,5α-THDOC) mirrored endogenous progesterone fluctuations and increased with EP treatment, while androstane NAS (e.g., 3α,5β-A, 3α,5α-A-diol) either inversely correlated with P4 or showed no cyclical pattern, decreasing with EP. Peripheral cytokines (IL-1β, IL-6, TNF-α) did not exhibit menstrual cycle-related fluctuations but were independently associated with suicidal ideation (SI), depressed mood, or anxiousness. Concurrent SSRI use correlated with lower androstane NAS levels.

Study Design

This was a double-blind, placebo-controlled, crossover randomized clinical trial (RCT; NCT03720847) involving 26 psychiatric outpatients with natural menstrual cycles and past-month SI. Participants underwent three experimental conditions (midluteal, perimenstrual, midfollicular phases) under both EP and placebo arms, timed using luteinizing hormone-surge ovulation tests. Serum samples were analyzed via GC/MS for NAS levels, and cytokines were measured using high-sensitivity multiplex assays.

Dosage & Administration

Participants received transdermal estradiol (0.1 mg/day) and oral micronized progesterone (200 mg/day) during the perimenstrual phase. Placebo was administered in the alternate arm. The crossover design allowed within-subject comparisons across conditions.

Results & Efficacy

P4-derived NAS: Increased significantly with EP administration (e.g., 3α,5α-THP: p = 0.003; 3α,5β-THP: p = 0.007; 3α,5α-THDOC: p = 0.014).
Androstane NAS: Decreased with EP (e.g., 3α,5β-A: p = 0.002; 3α,5α-A-diol: p = 0.011).
Cytokines: No cyclical patterns observed, but higher IL-6 levels predicted SI (β = 0.41, p = 0.032), and TNF-α predicted anxiousness (β = 0.49, p = 0.011).
SSRI Interaction: SSRI users had 30–40% lower androstane NAS levels (p < 0.05 for all).

Limitations

Small sample size: Only 26 participants, limiting generalizability.
Short duration: Single perimenstrual intervention period; long-term effects unknown.
Population specificity: Focused on psychiatric outpatients with SI, not healthy or non-suicidal individuals.
No direct Pregnenolone supplementation: Studied endogenous NAS precursors but did not test exogenous Pregnenolone.
Exploratory nature: Findings are hypothesis-generating, requiring replication in larger cohorts.

Clinical Relevance

While the study did not directly test Pregnenolone supplementation, it highlights the importance of hormonal fluctuations in modulating NAS pathways and cytokines associated with SI. For psychiatric patients with perimenstrual worsening of symptoms, EP therapy may stabilize GABAergic activity via P4-derived NAS. However, these results do not support Pregnenolone as a standalone intervention for SI. Clinicians should consider menstrual cycle phase in treatment planning and note potential interactions between hormonal therapies and SSRIs. Future research on NAS-targeted therapies, including Pregnenolone’s role in steroidogenesis, may inform personalized approaches for mood disorders.

Note: This analysis focuses on the study’s findings related to pregnenolone as a precursor in NAS pathways, not exogenous Pregnenolone supplementation. The intervention was estradiol/progesterone, not Pregnenolone.