Prasterone

Limits on what this shows

• Key negative/null findings: The rat dose-response study found no uncoupling of ADP/O ratios at any dose, a genuine boundary finding within the stimulatory body of evidence itself (respiration increased without loss of coupling efficiency).
• At-risk subgroups: Not established in humans at vaginal-insert-equivalent systemic exposure in any study located, in either direction.
• Counter-evidence on record: The roughly three-log concentration gap between Intrarosa's own labeled systemic exposure and the in vitro concentration at which complex I inhibition occurs is the primary evidence against the toxic-direction extrapolation applying to this product. The stimulatory rat and human data, while more encouraging in direction, also do not match this product's route or dose and should not be presented as evidence Intrarosa itself improves mitochondrial function.

Regulatory status

Not addressed in the Intrarosa label.

Population evidence

Protective/stimulatory: a rat dose-response study (subcutaneous DHEA 0.1, 0.2, 1.0, and 2.0 mg/kg body weight daily for 7 days; title "Effect of dehydroepiandrosterone (DHEA) treatment on oxidative energy metabolism in rat liver and brain mitochondria. A dose-response study," ScienceDirect, ScienceDirect PII S0009912006002815) found dose-dependent, tissue-specific stimulation of state 3 respiration, increased cytochrome aa3 and b content, increased glutamate dehydrogenase and succinate-DCIP reductase activity, and increased mitochondrial ATPase activity, without uncoupling ADP/O ratios at any dose tested; author names were not retrieved this session (disclosed below). Separately, a human study of infertile women undergoing IVF (Nutrients 2021, PMID 34371958, "Dehydroepiandrosterone Shifts Energy Metabolism to Increase Mitochondrial Biogenesis in Female Fertility with Advancing Age") found DHEA-treated patients produced more, higher-quality day-3 embryos and had improved pregnancy rates, with the proposed mechanism being enhanced oxidative phosphorylation and mitochondrial oxygen consumption in ovarian cumulus cells, described by the authors as a shift from anaerobic to aerobic metabolism. Inhibitory: Safiulina, Peet, Seppet, Zharkovsky, and Kaasik 2006 (Toxicological Sciences, PMID 16849397, DOI 10.1093/toxsci/kfl064) found DHEA suppresses mitochondrial respiration via complex I inhibition in permeabilized neurons at concentrations around 13 μM, and mice fed a 0.6% DHEA diet for three months showed significant neuronal loss in cerebral cortex and hippocampus, reduced dopamine metabolism, and motor impairment.

Mechanism

Concentration-dependent, bidirectional. The named inhibitory mechanism (complex I suppression) requires roughly 13 μM; Intrarosa's own labeled prasterone Cmax of 4.42 ng/mL converts to approximately 15 nM, about 850-fold below that threshold. The stimulatory rat data used systemic subcutaneous dosing (0.1 to 2.0 mg/kg), also a different route and substantially higher systemic delivery than a 6.5 mg local vaginal insert with roughly 15 nM peak systemic exposure produces.

Counter-evidence held on record

This is genuinely conflicting mechanistic literature about the DHEA molecule at concentrations mostly well above what Intrarosa's own label reports reaching systemically. Neither a "boosts your mitochondria" marketing claim nor a "damages your mitochondria" safety concern is supported at Intrarosa's actual labeled exposure. No monitoring or supplement action is indicated.

Limits on what this shows

• Key negative/null findings: The Diabetes Care RCT is itself the key finding that argues against the G6PD-inhibition-causes-oxidative-harm hypothesis translating into net human harm, at least at oral 50 mg dosing.
• At-risk subgroups: Not established at Intrarosa's systemic exposure in either direction; the diabetic-patient population studied for the protective signal is not Intrarosa's labeled population.
• Counter-evidence on record: The RCT above directly counters the pro-oxidant mechanistic concern. In the other direction, no study located tested oxidative-stress markers at Intrarosa's actual vaginal dose, so the protective RCT finding cannot be assumed to carry over either.

Regulatory status

Not addressed in the Intrarosa label; no oxidative-stress marker was measured in either pivotal trial reviewed.

Population evidence

Mechanism (pro-oxidant potential): Schwartz and Pashko 2004 (PMID 15177053) describes DHEA as "a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase"; Gordon, Mackow, and Levy 1995 (PMID 7726568) characterizes the steroid-G6PD binding mechanism; both are Tier B pharmacology/enzymology sources using DHEA itself, not this drug's route or dose. Counter-evidence (net antioxidant benefit): a randomized, double-blind, placebo-controlled trial (Diabetes Care 2007;30(11):2922-2929, DOI 10.2337/dc07-1110), n=40 (20 recently diagnosed, diet-controlled type 2 diabetic patients and 20 matched healthy controls), oral DHEA 50 mg once daily at 0800h for 12 weeks, found plasma ROS fell from 372.3±66.6 to 183.0±12.1 UF/mL (-53%, p<0.05), hydroxynonenal fell from 6.40±0.81 to 3.17±0.42 μmol/L (-47%, p<0.001), glutathione rose from 60.7±2.0 to 85.7±2.4 μg/mL (+38%, p<0.01), and the advanced-glycation-end-product marker pentosidine fell 50% (p<0.001), with parallel changes in peripheral blood mononuclear cells. This is Tier A/B human interventional data for DHEA specifically, but oral route, 50 mg dose (roughly 650-fold the systemic exposure Intrarosa's own label reports), and a diabetic/healthy-adult population, not postmenopausal women using a vaginal insert.

Mechanism

G6PD inhibition would be expected to reduce NADPH-dependent glutathione regeneration and increase oxidative stress; the human interventional data shows the opposite net effect at oral 50 mg dosing, suggesting either the G6PD mechanism is not dominant in vivo at that exposure, or it is outweighed by other DHEA-linked antioxidant pathways not characterized in the sources reviewed this session.

Counter-evidence held on record

Do not present this as "Intrarosa depletes your antioxidants" (the mechanistic worry) or as "Intrarosa is an antioxidant" (the RCT finding); neither claim has been tested at this product's actual route and dose, and the two bodies of evidence that do exist for DHEA point in opposite directions. No antioxidant supplementation or monitoring is indicated by either.

Limits on what this shows

• Key negative/null findings: No significant DHEA-S/hemoglobin association was found in women in the 149-person cohort, directly relevant since Intrarosa's population is exclusively postmenopausal women.
• At-risk subgroups: None identified; if anything this is a reverse/protective-direction signal, and it is weakest or absent in the sex that uses this product.
• Counter-evidence on record: Absence of the association in women (above); cross-sectional design cannot exclude confounding by general health status; Intrarosa's own labeled systemic testosterone rise is small (Cmax 0.15 ng/mL, +21% trough at 12 weeks) compared to what the higher-DHEA-S men in these correlational cohorts likely have circulating.

Regulatory status

Not addressed in the Intrarosa label; no iron-status marker was measured in either pivotal trial.

Population evidence

A retrospective cohort study (Journal of the Endocrine Society, abstract SAT-LB068, 2019, PMC6552163), n=149 (54 men, 95 women, mean age 52.7±17.6), found serum DHEA-S positively correlated with hemoglobin (R=0.419, p<0.01) and hematocrit (R=0.375, p<0.01) in men, with no significant association in women; the authors concluded "reduced DHEAS secretion inhibits erythropoietic activity in aging men." A separate cross-sectional cohort (Frontiers in Endocrinology 2025, DOI 10.3389/fendo.2025.1708007), n=1,341 Korean adults (69.4% female), found DHEA-S positively associated with hemoglobin (p<0.001) independent of age and BMI, and the cortisol/DHEA-S ratio negatively associated with hemoglobin (p=0.006); this cohort was not stratified by sex in the results retrieved. Handala et al. 2017 (described fully in the ATP production entry) found DHEA at 200 μM protects human erythrocytes against ribavirin-induced hemolysis, a drug-interaction context rather than a baseline iron-status effect. All three sources measured or manipulated DHEA/DHEA-S, not prasterone administered vaginally, and none used Intrarosa's population or route.

Mechanism

Proposed as androgen-driven erythropoietic stimulation, consistent with the well-established general pharmacology of androgens (including testosterone, a DHEA metabolite) as erythropoiesis stimulants; however, the cohort studies are observational and measure endogenous hormone levels, not administered drug, so causation is not established (see Hard Rule 6).

Counter-evidence held on record

This is not evidence that Intrarosa raises hemoglobin or treats anemia. It is observational endogenous-hormone correlation, strongest in men, and Intrarosa's own labeled systemic testosterone rise is modest. No iron-related monitoring or supplementation is indicated by this evidence.

Limits on what this shows

• Why no grade: Both conditions for ungraded were met. No Tier B or Tier C evidence exists showing DHEA or prasterone affects copper status: the only copper-DHEA literature located runs in the reverse direction, which this protocol's Hard Rule 4 excludes from grading a drug-caused nutrient effect. No circulating consumer claim about prasterone, Intrarosa, or DHEA affecting copper was identified in either of the two major consumer drug-information sources checked (WebMD's DHEA monograph, Drugs.com's Intrarosa monograph), both of which state no known nutrient or mineral interaction exists.

Reverse-direction evidence found (excluded from grading)

Klevay and Christopherson 2000 (Journal of Trace Elements in Medicine and Biology, ScienceDirect PII S0946672X00800024), a rat study, found copper deficiency decreased serum DHEA by approximately 50%, concluding "people who associate higher serum concentrations of DHEA with health probably should eat a diet adequate in copper." A separate case-control study (Biological Trace Element Research 2011, PMID 21384145, "Impact of Trace Element Changes on Dehydroepiandrosterone Sulfate in Healthy and Diabetic States among Middle-Age and Elderly Egyptians") examined how changes in trace elements including cadmium, chromium, and zinc affect DHEA-S levels in Egyptian adults; direction again runs trace-element-to-hormone, not hormone-to-trace-element, and the specific elements listed did not include copper by name in the metadata retrieved. Neither source supports grading a copper effect of this drug.

Tooling disclosure

A JACC article titled "Copper, Coronary Heart Disease, and Dehydroepiandrosterone" (DOI 10.1016/j.jacc.2015.02.065) was identified as potentially relevant but could not be accessed this session: the publisher page returned an HTTP 403 error, and two subsequent attempts to retrieve its abstract via the OpenAlex works API were rejected with HTTP 429 rate-limiting. This source's direction and relevance to prasterone are therefore unconfirmed, not ruled out, and this is a genuine access gap rather than a confirmed absence of evidence; a future revision should re-check it specifically. Beyond this one article, Copper was searched across DailyMed, PubMed search-listing pages, the OpenAlex works API, and the two consumer-claim sources named above, with multiple query phrasings, before this conclusion was reached.

Limits on what this shows

• Key negative/null findings: None located; no oral-route, low-dose, or vaginal-route DHEA gut-microbiome study of any kind, in a non-disease-model context, was found.
• At-risk subgroups: None established for the postmenopausal, local-vaginal-route population Intrarosa treats; the rodent model population (young, disease-induced) does not correspond to Intrarosa's labeled use.
• Counter-evidence on record: The enormous dose gap between a protocol designed to produce supraphysiologic hyperandrogenism and a 6.5 mg local vaginal dose reaching roughly 15 nM systemic peak is itself the main argument against translatability, alongside the complete absence of any low-dose or local-route DHEA gut-microbiome study.

Regulatory status

Not addressed in the Intrarosa label; no microbiome endpoint of any kind was measured in either pivotal trial.

Population evidence

Multiple 2022-2026 rodent studies use DHEA at supraphysiologic, subcutaneous, disease-induction doses to create a polycystic-ovary-syndrome phenotype and report accompanying gut microbiota changes as part of that phenotype: Huang, Chen, Xiang, et al. 2022 (PMID 35334358), "Gut microbiota dysbiosis-derived macrophage pyroptosis causes polycystic ovary syndrome via steroidogenesis disturbance and apoptosis of granulosa cells," in a DHEA-induced rat model; Chen, Lu, Lin, et al. 2025 (PMID 41360922), "Gut-ovary axis and multiomic insights into PCOS in a DHEA-induced rat model"; Zhang, Chen, Zhou, et al. 2025 (PMID 40989123), gut microbiota dysbiosis in a DHEA-plus-high-fat-diet-induced PCOS mouse model. These were identified via PubMed search-listing pages (titles, authors, years, PMIDs confirmed); full abstracts were not individually opened this session, and specific dose figures for each study were not independently re-verified (disclosed in Sources).

Mechanism

Not clearly delineated at the title/listing level; broadly framed in this literature as hyperandrogenism-driven gut dysbiosis contributing to a PCOS phenotype, not as a direct toxic effect of DHEA on gut flora at ordinary or therapeutic exposure.

Counter-evidence held on record

This is disease-model rodent data at doses that do not represent Intrarosa's actual exposure in any sense and should not be read as evidence that Intrarosa disrupts gut flora. Note also that this required category is specifically about the gut microbiome; Intrarosa's own labeled Section 14 data (vaginal pH falling from a mean of roughly 6.4-6.5 to roughly 5.4-5.4 by week 12, alongside increased superficial and decreased parabasal cells on vaginal cytology) describes a real, favorable, Tier A, drug-specific change to the local vaginal microenvironment, a different anatomical site not covered by this required category and not a nutrient finding, so it is not filed as a graded entry here but is worth this note for accuracy. No probiotic or gut-focused monitoring is indicated by the evidence reviewed.

Limits on what this shows

• Key negative/null findings: None located beyond the bidirectionality itself; no study tested ATP status with DHEA alone (without a second stressor drug) at a concentration near Intrarosa's systemic exposure.
• At-risk subgroups: Not established at Intrarosa's systemic exposure.
• Counter-evidence on record: The same roughly three- to four-log concentration gap documented in the Mitochondrial burden entry applies here. Additionally, the erythrocyte-protective finding was measured only in the presence of a co-administered stressor drug (ribavirin), not as a baseline effect of DHEA alone on ATP status.

Regulatory status

Not addressed in the Intrarosa label.

Population evidence

Handala et al. 2017 (PMID 28890388, ScienceDirect PII S0166354217304588), human erythrocytes from 5 healthy donors ex vivo: DHEA at 200 μM protected against ribavirin-induced ATP depletion (37% of ATP remaining with DHEA added versus 1% with ribavirin alone, p<0.01), reduced cell shrinkage (10% versus 40%, p<0.01), and reduced hemolysis at 72 hours (34% versus 46.5%, p<0.01) by non-competitively inhibiting G6PD and interrupting the pentose phosphate pathway. The same paper notes that 50 mg daily oral DHEA supplementation maintains levels around 10 μM in young adults, so the protective concentration tested is roughly 20-fold above even the oral-supplement level and roughly 13,000-fold above Intrarosa's own labeled systemic Cmax. Yang, Jeng, Ho, and Hu 2002 (Life Sciences 70(17):1979-1988, PMID 12148690), mouse BV-2 microglial cells in vitro: ATP depletion was identified as an important factor in DHEA-induced growth inhibition and apoptosis; the specific DHEA concentration used could not be retrieved this session (disclosed below). The Nutrients 2021 IVF cumulus-cell study (PMID 34371958, described fully in the Mitochondrial burden entry) also reported enhanced oxidative-phosphorylation-linked energy production, and the rat dose-response study above reported stimulated mitochondrial ATPase activity at low systemic doses.

Mechanism

DHEA's G6PD inhibition shunts glucose away from the pentose phosphate pathway; in the erythrocyte/ribavirin model this paradoxically preserves ATP by preserving glycolytic flux, while in BV-2 microglial cells high-dose DHEA is associated with net ATP depletion. The direction appears to depend on cell type, baseline metabolic demand, and concentration, not a single uniform drug effect.

Counter-evidence held on record

Do not present the erythrocyte-protective finding as "Intrarosa protects your cellular energy"; it is a laboratory finding about DHEA co-incubated with a different antiviral drug at a concentration Intrarosa's own label never approaches systemically. This entry shares its underlying concentration-gap logic and one source (the Nutrients 2021 cumulus-cell study) with Mitochondrial burden above; see the Overlap map. No supplement or monitoring action is indicated.

Limits on what this shows

• Key negative/null findings: Same as Iron: no significant association in women in the 149-person cohort.
• At-risk subgroups: None identified for Intrarosa's population.
• Counter-evidence on record: Same as Iron: absence of effect in women, cross-sectional confounding, and Intrarosa's modest labeled systemic testosterone rise relative to the cohorts studied.

Regulatory status

Not addressed in the Intrarosa label; no oxygen-delivery marker (hemoglobin, hematocrit, arterial oxygenation) was measured in either pivotal trial.

Population evidence

Same two cross-sectional cohorts as the Iron entry: PMC6552163 (n=149, hemoglobin R=0.419 and hematocrit R=0.375 in men only, p<0.01) and the Frontiers 2025 Korean cohort (n=1,341, DHEA-S positively associated with hemoglobin p<0.001; cortisol/DHEA-S ratio negatively associated with hemoglobin p=0.006).

Mechanism

Same androgen-driven erythropoiesis hypothesis as Iron; observational, not interventional, so this describes a correlation with oxygen-carrying capacity markers, not a demonstrated effect on tissue oxygen delivery or utilization.

Counter-evidence held on record

This entry rests on the identical sources and mechanism as Iron above (see Overlap map); it is kept as a separate entry per this protocol's Hard Rule 7, not as independent confirmation. No monitoring or supplementation is indicated.