Levonorgestrel

Limits on what this shows

• Key negative/null findings: Khokha R, Walton PA, Possmayer F, Wolfe B. "Effects of levonorgestrel on enzymes responsible for synthesis of triacylglycerols in rat liver" (1987, PMID 3103689, Biochimica et Biophysica Acta), also a levonorgestrel-specific rat liver study, found hepatic mitochondrial enzyme activity for the glycerol-3-phosphate acyltransferase pathway unchanged with levonorgestrel treatment, while the corresponding microsomal enzyme activity fell by 26%. This is a genuine null finding for that specific mitochondrial enzyme, though it measured a different endpoint, a lipid-synthesis enzyme, not ultrastructure, glutathione, or ATP synthesis, than Kretzschmar et al.
• At-risk subgroups: Not established in humans. Both supporting studies are 1980s rat hepatic models; the 10 mg/kg dose producing mitochondrial lesions is far above any human therapeutic-equivalent exposure (Plan B One-Step is a single 1.5 mg dose in an average adult, on the order of 0.02-0.03 mg/kg; Mirena releases roughly 20 mcg/day initially), which sharply limits translatability to labeled dosing of either product.
• Counter-evidence on record: The Khokha et al. null finding above; also the explicit dose-dependence within Kretzschmar et al. itself, since no mitochondrial lesion was reported at 1 mg/kg, only at 10 mg/kg, arguing against a low-dose or therapeutic-dose mitochondrial structural effect.

Regulatory status

Not addressed in either label reviewed.

Population evidence

Kretzschmar M, Giese R, Franke H, Machnik G, Klinger W. "Hepatic actions of levonorgestrel: correlations between biochemical and morphological findings" (1989, PMID 2500261, Chemico-Biological Interactions 70:157-166), a Tier B rat mechanistic study using levonorgestrel specifically, not combined with estrogen. At 10 mg/kg body weight, levonorgestrel produced "distinct lesions of the mitochondria" in centrilobular hepatocytes on ultrastructural examination, together with a reduction in total hepatic glutathione that was more pronounced in the mitochondrial fraction than in other compartments. At the lower 1 mg/kg dose tested in the same study, only cytochrome P-450 content fell; no mitochondrial ultrastructural lesion was reported at that dose, indicating a dose-dependent effect.

Mechanism

The study links the ultrastructural mitochondrial injury to preferential depletion of mitochondrial glutathione, a redox-buffering correlation rather than a named receptor or metabolic pathway; this is a structural/redox association in a high-dose rodent model, not a demonstrated mechanism in human hepatic or extrahepatic tissue.

Counter-evidence held on record

This is high-dose rat hepatic toxicology data, not a demonstrated effect at human therapeutic dosing or in human tissue. Do not present this as evidence that levonorgestrel damages mitochondria at labeled doses. No supplement or monitoring action is indicated by this evidence.

Limits on what this shows

• Key negative/null findings: None located; the human comparative study's direction is unknown to this review (see access note), so it cannot be reported as either a positive or null finding.
• At-risk subgroups: Not established.
• Counter-evidence on record: None located; flagged for re-check when the source becomes accessible.

Regulatory status

Not addressed in either label reviewed.

Population evidence

Buyuk GN et al. 2021, "Copper and levonorgestrel containing intrauterine devices: comparison of their effect on oxidative stress markers" (PMID 33594922), a human comparative study of copper-IUD vs LNG-IUD users. Access note: the full abstract could not be retrieved this session despite repeated attempts across pubmed.ncbi.nlm.nih.gov, europepmc.org, the Europe PMC REST API, and the Semantic Scholar API (HTTP 429 and bot-verification responses on every attempt); only the title and PubMed indexing were available, so direction and magnitude of the oxidative-marker findings are not asserted here.

Mechanism

Meric Turgut et al. 2025 (PMID 41012385), "Integrating Experimental Toxicology and Machine Learning to Model Levonorgestrel-Induced Oxidative Damage in Zebrafish," is a Tier B animal mechanistic study, but in a non-mammalian aquatic species at environmental/toxicology-range exposure, which limits translatability to human therapeutic dosing.

Counter-evidence held on record

This entry documents that drug-specific evidence exists and should be re-reviewed with full-text access, not that levonorgestrel increases or decreases oxidative stress. Do not present this as a confirmed antioxidant-depletion claim.

Limits on what this shows

• Key negative/null findings: Perello-Capo et al. 2023 (PMID 37487868) found no significant difference in hemoglobin or hematocrit between a lower-dose 13.5 mg levonorgestrel IUD and a copper IUD, indicating the hematologic benefit is dose- and/or baseline-bleeding-dependent, not a universal levonorgestrel effect. An older Finnish-language reference (Luukkainen and Nilsson 1987, PMID 3331147) is indexed as noting a hemoglobin/iron decrease despite amenorrhea in some hormonal-coil users; this is an older, lower-confidence source (language-limited abstract, superseded device generation) and is recorded here as a genuine, unresolved counter-signal rather than omitted.
• At-risk subgroups: Benefit is specific to women with baseline heavy menstrual bleeding using the 52 mg device; not established for the 13.5–19.5 mg lower-dose systems (Kyleena, Skyla) or for Plan B single-dose emergency contraception, which has no chronic exposure and no plausible iron-status effect.
• Counter-evidence on record: See Key negative/null findings above; also note active-comparator design (Mirena vs medroxyprogesterone acetate, or vs copper IUD) does not test against no treatment, so part of the apparent benefit reflects the comparator's own bleeding profile, not an absolute baseline.

Regulatory status

Mirena is FDA-indicated for treatment of heavy menstrual bleeding for up to 5 years. Labeled trial (n=79 Mirena vs n=81 medroxyprogesterone acetate, 6 cycles, MBL ≥80 mL by alkaline hematin method) showed statistically significantly greater reduction in menstrual blood loss with Mirena; roughly 9 of 10 treated successfully with blood loss reduced by more than half.

Population evidence

Lowe RF, Prata N. "Hemoglobin and serum ferritin levels in women using copper-releasing or levonorgestrel-releasing intrauterine devices: a systematic review" (2013, PMID 23122687) is stratified to LNG-IUS specifically. Full abstract could not be retrieved this session (repeated access blocks, see Sources); title and indexing confirm the review's direct focus on hemoglobin/ferritin outcomes in LNG-IUS users compared with copper-IUD users.

Mechanism

Reduced menstrual blood loss lowers cumulative iron loss; not a direct pharmacologic effect on iron absorption, transport, or storage.

Counter-evidence held on record

This is a therapeutic, protective effect tied to a specific FDA-labeled indication (heavy menstrual bleeding) and device dose, not a general reason to expect iron benefits from levonorgestrel use, and not a signal to add iron supplementation. Women who switch from heavy bleeding to a levonorgestrel IUD and were previously on iron supplementation may need that reassessed by their prescriber, not increased.

Limits on what this shows

• Key negative/null findings: Perello-Capo et al. 2023 (PMID 37487868): no significant hemoglobin or hematocrit difference between 13.5 mg LNG-IUD and copper IUD, again indicating a dose-bounded effect.
• At-risk subgroups: Relevant only to heavy-menstrual-bleeding patients on the 52 mg device; no plausible oxygen-delivery effect from single-dose Plan B.
• Counter-evidence on record: Same active-comparator limitation as the Iron entry; also note per Hard Rule 2 that reduced bleeding is the drug's own intended pharmacologic effect for this indication, so the entry is written here as a downstream hematologic consequence of that effect, not as an independent nutrient claim.

Regulatory status

Same Mirena heavy-menstrual-bleeding indication and trial data as the Iron entry (DailyMed setid dcbd6aa2). The label itself does not report specific hemoglobin change figures in the sections reviewed; hemoglobin is discussed only via the secondary literature below.

Population evidence

Lowe and Prata 2013 (PMID 23122687), stratified to LNG-IUS, reviews hemoglobin specifically alongside ferritin. See access note under the Iron entry; full abstract not retrievable this session.

Mechanism

Indirect: less menstrual blood loss preserves red-cell mass and hemoglobin; this is a downstream consequence of the drug's approved bleeding-reduction effect, not a direct action on erythropoiesis, hemoglobin synthesis, or arterial oxygenation.

Counter-evidence held on record

This entry shares its underlying evidence with the Iron entry above (see Overlap map). It describes a bounded, indication-specific benefit, not a general "boosts oxygen delivery" claim, and carries no supplementation implication in either direction.