Histrelin implant

Limits on what this shows

• Key negative/null findings: "There was no change in mitochondrial function measured ex vivo or in vivo after six months of ADT," a direct null finding that tempers the proteomic signal: pathway-level expression moved, but measured respiratory function, including in vivo ATP-generating capacity, did not, over this timeframe.
• At-risk subgroups: Patients with lower baseline mitochondrial respiration/ATP Max showed worse body-composition and performance outcomes during treatment, suggesting baseline fitness may modify vulnerability, though this was not a randomized comparison, and applies to men on ADT generally, the population matching Vantas, not Supprelin LA.
• Counter-evidence on record: Cohort test limitation: the source confirms "GnRH agonist" as the ADT class for 93.2% of patients but does not name histrelin specifically among the agents used, so this is Tier C (class-level) for histrelin, capping the grade at yellow rather than orange or red.

Regulatory status

Not addressed on either label.

Population evidence

This review independently opened and confirmed the source directly: longitudinal cohort, 60 prostate cancer patients starting ADT (59 completing baseline, 57 at 3 months, 55 at 6 months), 93.2% prescribed a GnRH agonist (agent not individually named). Gene Set Enrichment Analysis of skeletal-muscle proteomics found the most downregulated pathways were related to mitochondrial function, with significant downregulation (P<0.01) of mitochondrial leading-edge proteins at 6 months. [5]

Mechanism

Plausible but not fully isolated: loss of testosterone's known role in supporting mitochondrial gene expression and biogenesis in skeletal muscle is the leading candidate, consistent with the finding's direction, but the source does not isolate testosterone loss as the specific driver, nor does it name histrelin individually among the GnRH agonists used.

Counter-evidence held on record

This entry shares its evidence base with the ATP production entry in the Fails verification section below; see the Overlap map. Do not present this as proof of measurable mitochondrial dysfunction: the same study's direct functional measurements (respiration, ATP Max) did not change. This finding is also specific to the adult ADT population and has no established relevance to children on Supprelin LA.

Limits on what this shows

• Key negative/null findings: None identified; the paywall and the 403 response on the publisher page limited independent verification of this study's full results.
• At-risk subgroups: Men with prostate cancer on unspecified antiandrogenic therapy (source population, predating histrelin's approval).
• Counter-evidence on record: No histrelin-specific or confidently class-inclusive oxidative-stress study was located across multiple search channels (WebSearch before budget exhaustion, WebFetch to the Crossref API). This is graded yellow at the low end of that tier given both the access limitation and the approval-timing gap.

Regulatory status

Not addressed on either label.

Population evidence

Iynem Alkan H, Alademir AZ, Obek C, Kural AR, Konukoglu D, Akcay T. The effect of prostate cancer and antiandrogenic therapy on lipid peroxidation and antioxidant systems. International Urology and Nephrology, 2003;36(1):57-62. This review independently confirmed the paper's full author list, journal, year, and page range via the Crossref API, but the DOI redirect to the publisher's page returned no accessible content, so the study's quantitative malondialdehyde, glutathione peroxidase/reductase, erythrocyte glutathione, and vitamin E results are not asserted here. [6] Tier C for histrelin, and notably for the entire GnRH-agonist class as tested: histrelin (Vantas) was not FDA-approved until October 2004, after this study's 2003 publication, so it is definitionally excluded from this cohort, a timing detail that makes this a class-level-at-best signal even for the drug class broadly.

Mechanism

Not drug-isolated in the accessible metadata. General plausibility rests on the broader literature linking sex-steroid loss to redox changes, the same hormonal-disturbance mechanism class underlying the bone and hematologic findings above, not a histrelin-specific or even confidently class-specific oxidative pathway.

Counter-evidence held on record

Access limitation and timing limitation both disclosed: this source's full quantitative results could not be verified, and histrelin itself was not yet FDA-approved when this study was conducted, so it cannot have studied histrelin even at a class level with certainty about which agents were included. Treat this entry as the weakest-supported yellow grade in this dossier.

Limits on what this shows

• Key negative/null findings: Serum iron itself did not decline in the leuprolide cohort, the single most important number for not recommending empiric iron supplementation on this evidence, and the source authors' own conclusion that hepcidin is not the primary anemia mechanism despite the statistical correlation.
• At-risk subgroups: None established for histrelin specifically; the only directly studied population is men on leuprolide-based ADT, a different drug within the same indication as Vantas.
• Counter-evidence on record: No histrelin-specific ferritin, hepcidin, or serum-iron study was located across multiple search channels (WebSearch, WebFetch to the Crossref API and to PubMed/Europe PMC search pages, the latter two blocked). This absence is disclosed as a genuine gap for histrelin specifically.

Regulatory status

Not addressed on either histrelin label as a drug effect on iron status.

Population evidence

This review independently opened and confirmed the source directly: prospective cohort, 70 men total (31 on leuprolide acetate 22.5 mg IM every 3 months versus 39 post-prostatectomy controls without ADT), 24-week follow-up, all with normal testosterone at enrollment. Serum iron did not significantly change (mean difference -1.1 µg/dL, 95% CI -11.9 to 9.7, P=0.837); ferritin rose by a mean difference of 60 ng/mL (95% CI 40 to 80, P<0.001) in the ADT group; hepcidin rose by a mean difference of 18 ng/mL (95% CI 10 to 25, P<0.001). [3] Tier C for histrelin: leuprolide, not histrelin, was the drug studied, though the population (adult men on ADT for prostate cancer) matches histrelin's own Vantas indication closely.

Mechanism

Proposed but explicitly qualified by the source's own authors: hepcidin-mediated downregulation of ferroportin would be expected to reduce iron release from macrophages/enterocytes to the marrow, but the study's own conclusion states the absence of reduced serum iron indicates hepcidin is not the primary driver of the associated anemia, which the authors instead attribute to reduced bone marrow erythroid cell production.

Counter-evidence held on record

This is a different-drug extrapolation of a possible retention/reduced-utilization pattern, not a confirmed histrelin finding and not an iron deficiency. Do not recommend iron supplementation for ADT-associated fatigue or anemia in men on Vantas based on this evidence; the source study's own authors conclude hepcidin is not even the primary mechanism in the drug it did study.

Limits on what this shows

• Key negative/null findings: None identified; the paywall limited independent verification of the study's full results in both this dossier and the companion goserelin dossier that first surfaced it.
• At-risk subgroups: None established in humans for any GnRH agonist; the source finding is in vitro chemistry, not a patient population.
• Counter-evidence on record: No human or in vitro copper study of histrelin specifically was located across multiple search channels (WebSearch, WebFetch to the Crossref API). Results returned for "histrelin copper zinc trace element" were unrelated general trace-element or histatin-peptide chemistry papers, not histrelin findings, and are not cited as supporting evidence.

Regulatory status

Not addressed on either label.

Population evidence

"Impact of the Cu(II) ions on the chemical and biological properties of goserelin: coordination pattern, DNA degradation, oxidative reactivity and in vitro cytotoxicity" (Walencik PK et al., Journal of Inorganic Biochemistry, 2017;175:167-178). This review independently confirmed the paper's title, full author list, journal, year, and page range via the Crossref API, but the publisher page returned no accessible content (closed access) when fetched directly, so the study's quantitative coordination-chemistry, DNA-degradation, and oxidative-reactivity results are not asserted here. [4] Tier B for goserelin; Tier C for histrelin, since a different class member, not histrelin, was studied.

Mechanism

Direct coordination chemistry in the source drug: Cu(II) ions bind goserelin's peptide structure, and the resulting complex is reported to have oxidative and DNA-damaging reactivity in vitro. Extrapolating this to histrelin is weaker than most class extrapolations in this series, because histrelin is a nonapeptide (nine amino acids) while goserelin is a decapeptide (ten amino acids) with a different C-terminal modification; the peptide backbone that reportedly coordinates copper in goserelin is not structurally identical in histrelin, so this entry explicitly flags a lower degree of structural confidence than a same-length-peptide extrapolation would carry.

Counter-evidence held on record

This is in vitro coordination chemistry between a different GnRH-agonist peptide and copper ions, not a finding about copper deficiency or excess in patients taking histrelin, and the structural mismatch between a nonapeptide and a decapeptide drug weakens the extrapolation further. It should not be read as evidence that histrelin depletes or elevates copper status in the body, and no copper-supplement recommendation follows from it.

Limits on what this shows

• Key negative/null findings: None identified in the accessible source text.
• At-risk subgroups: Men on ADT generally; the source's own framing links the dysbiosis to frailty risk, an outcome-level concern rather than a nutrient-level one, which this entry does not conflate with the microbiome finding itself.
• Counter-evidence on record: No histrelin-specific gut microbiome study was located across multiple search channels (WebSearch, WebFetch to the Crossref API, and to the Europe PMC REST API, which returned repeated HTTP 429 responses). This absence is disclosed as a genuine gap for histrelin specifically.

Regulatory status

Not addressed on either label.

Population evidence

This review independently opened and confirmed the source directly: 24-week observational study, prostate cancer patients undergoing ADT with sequential fecal sampling at baseline and 1, 4, 12, and 24 weeks post-treatment; 23 patients completed the study. Alpha- and beta-diversity of gut microbiota decreased significantly at 24 weeks (P=0.017, P<0.001), with increased Proteobacteria, Gammaproteobacteria, Pseudomonadales, and Pseudomonas abundance, and significant changes in urea, lactate, butyrate, 2-hydroxyisobutyrate, and S-adenosylmethionine concentrations (P<0.05); Proteobacteria abundance correlated positively with lactate (R=0.49, P<0.01). [7] Tier C for histrelin: the specific ADT agents were not named in the accessible text.

Mechanism

Proposed by the study authors: testosterone decline indirectly alters the gut environment, producing dysbiosis that may contribute to increased frailty risk. Plausible for any testosterone-suppressing GnRH agonist including histrelin's Vantas formulation, but not isolated to histrelin specifically, and this mechanism has no established relevance to the estrogen-suppressed pediatric CPP population on Supprelin LA.

Counter-evidence held on record

This is class-level evidence for androgen deprivation therapy in elderly men generally, not a histrelin-specific finding, and it has no demonstrated relevance to children on Supprelin LA, a different population and a different suppressed hormone axis (estrogen/testosterone at prepubertal, not castrate-in-an-aging-body, levels).

Limits on what this shows

• Key negative/null findings: The Supprelin LA (pediatric CPP) label states directly that its pivotal 1-year, 36-patient trial found "no clinically meaningful findings in standard clinical hematology and chemistry tests," a genuine null finding specific to histrelin in the pediatric population, a different population and formulation context from the adult Vantas anemia signal, and one this dossier keeps clearly separated rather than averaging together.
• At-risk subgroups: Adult men on Vantas for prostate cancer. The pediatric CPP population on Supprelin LA shows no comparable hematologic signal in its own labeled or trial-reported data.
• Counter-evidence on record: No second independent Tier A source naming histrelin specifically was located to corroborate or quantify the under-2% label figure, which is why this is capped at orange rather than red; a stronger, two-study red-tier hemoglobin-decline signal exists for leuprolide specifically in this same drug class (a different drug, reviewed separately), and is not carried into this entry as histrelin's own evidence.

Regulatory status

The FDA VANTAS label lists anemia under Blood and Lymphatic System Disorders in the Adverse Reactions section, occurring in under 2% of patients in the clinical trial and postmarketing experience pooled for that section. No numeric hemoglobin or hematocrit decline is quantified, and no hematologic monitoring schedule is specified.

Population evidence

The pivotal registration trial underlying the Vantas label (Schlegel PN et al., Efficacy and Safety of Histrelin Subdermal Implant in Patients With Advanced Prostate Cancer, Journal of Urology, 2006) is the presumed source of this frequency figure. This review independently confirmed the paper's title, authors (Peter N. Schlegel and the Histrelin Study Group), journal, and year via the Crossref API, but its full text returned a 403 error at doi.org, ResearchGate, and a Drug Design, Development and Therapy review that cites it, so this dossier does not assert any quantitative hemoglobin/hematocrit value from that trial beyond the label's own under-2% frequency band. [1]

Mechanism

Not quantified for histrelin specifically in any source this review could open. The mechanism established for this drug class in a leuprolide-specific cohort (loss of testosterone's stimulatory effect on marrow erythroid progenitors, plus hepcidin-mediated reduced iron mobilization; see the Iron entry below) is presumed to apply given histrelin's equivalent castrate-level testosterone suppression, but this is class-level plausibility carried into the mechanism discussion, not a histrelin-specific mechanistic finding.

Counter-evidence held on record

This is a low-frequency, unquantified label signal in adult men, not an established nutritional or iron-deficiency anemia, and it has no counterpart in the pediatric Supprelin LA hematology data, which was explicitly reported as unremarkable. Do not present iron or B-vitamin supplementation as a routine fix for this signal; see the Iron entry below, which is class-extrapolated from a different GnRH agonist (leuprolide) and shows a retention, not deficiency, pattern in that drug's own cohort.