{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "2003602",
      "year": "1991",
      "title": "Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans.",
      "doi": "10.1152/ajpendo.1991.260.3.E499",
      "url": "https://pubmed.ncbi.nlm.nih.gov/2003602/",
      "interpretation": "Local GH can change acute forearm protein kinetics; this establishes physiology, not lasting recovery."
    },
    {
      "pmid": "1550219",
      "year": "1992",
      "title": "Effect of growth hormone and resistance exercise on muscle growth in young men.",
      "doi": "10.1152/ajpendo.1992.262.3.E261",
      "url": "https://pubmed.ncbi.nlm.nih.gov/1550219/",
      "interpretation": "GH-plus-training trial in young men adds mass and whole-body synthesis without extra muscle-strength benefit."
    },
    {
      "pmid": "8156094",
      "year": "1994",
      "title": "Three years of growth hormone treatment in growth hormone-deficient adults: near normalization of body composition and physical performance.",
      "doi": "10.1530/eje.0.1300224",
      "url": "https://pubmed.ncbi.nlm.nih.gov/8156094/",
      "interpretation": "Long-term GH-deficiency replacement illustrates a separate baseline-deficiency indication."
    },
    {
      "pmid": "7864103",
      "year": "1995",
      "title": "Effect of growth hormone and resistance exercise on muscle growth and strength in older men.",
      "doi": "10.1152/ajpendo.1995.268.2.E268",
      "url": "https://pubmed.ncbi.nlm.nih.gov/7864103/",
      "interpretation": "Older-adult matched-training comparison shows additional GH mass/water change without added strength."
    },
    {
      "pmid": "9005976",
      "year": "1997",
      "title": "Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men.",
      "doi": "10.1016/s0026-0495(97)90174-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/9005976/",
      "interpretation": "Older-adult GHRH before-after findings combine selected functional changes with null metabolic and composition measures; controls remain limited."
    },
    {
      "pmid": "9849822",
      "year": "1998",
      "title": "Ipamorelin, the first selective growth hormone secretagogue.",
      "doi": "10.1530/eje.0.1390552",
      "url": "https://pubmed.ncbi.nlm.nih.gov/9849822/",
      "interpretation": "Ipamorelin receptor profiling and animal hormone selectivity establish a mechanistic starting point."
    },
    {
      "pmid": "10496658",
      "year": "1999",
      "title": "Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers.",
      "doi": "10.1023/a:1018955126402",
      "url": "https://pubmed.ncbi.nlm.nih.gov/10496658/",
      "interpretation": "Human ipamorelin pharmacodynamics show GH stimulation without physical recovery endpoints."
    },
    {
      "pmid": "10477776",
      "year": "1999",
      "title": "Increased mortality associated with growth hormone treatment in critically ill adults.",
      "doi": "10.1056/NEJM199909093411102",
      "url": "https://pubmed.ncbi.nlm.nih.gov/10477776/",
      "interpretation": "Two critically ill adult trials demonstrate high-dose GH mortality harm in a distinct severe clinical context."
    },
    {
      "pmid": "11162489",
      "year": "2001",
      "title": "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues.",
      "doi": "10.1006/bbrc.2000.4065",
      "url": "https://pubmed.ncbi.nlm.nih.gov/11162489/",
      "interpretation": "Mouse secretagogue adiposity effects challenge assuming all actions are explained by GH."
    },
    {
      "pmid": "12425705",
      "year": "2002",
      "title": "Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial.",
      "doi": "10.1001/jama.288.18.2282",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12425705/",
      "interpretation": "Older-adult factorial GH/sex-steroid study shows sex- and endpoint-specific findings alongside adverse effects."
    },
    {
      "pmid": "12519419",
      "year": "2003",
      "title": "Recombinant human growth hormone treatment in elderly patients undergoing elective total hip replacement.",
      "doi": "10.1046/j.1365-2265.2003.01700.x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12519419/",
      "interpretation": "Controlled perioperative GH produces selected walking and muscle-preservation benefit with frequent dose-related side effects."
    },
    {
      "pmid": "16352683",
      "year": "2006",
      "title": "Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults.",
      "doi": "10.1210/jc.2005-1536",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16352683/",
      "interpretation": "Blinded CJC-1295 ascending-dose human trials demonstrate prolonged GH/IGF-I activity."
    },
    {
      "pmid": "17018654",
      "year": "2006",
      "title": "Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog.",
      "doi": "10.1210/jc.2006-1702",
      "url": "https://pubmed.ncbi.nlm.nih.gov/17018654/",
      "interpretation": "CJC pulsatility measurements refine endocrine engagement without adding a clinical recovery trial."
    },
    {
      "pmid": "18981485",
      "year": "2008",
      "title": "Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial.",
      "doi": "10.7326/0003-4819-149-9-200811040-00003",
      "url": "https://pubmed.ncbi.nlm.nih.gov/18981485/",
      "interpretation": "MK-677 increases hormones and fat-free mass while measured function remains unchanged; glycemic monitoring supplies a safety boundary."
    },
    {
      "pmid": "19386527",
      "year": "2009",
      "title": "Activation of the GH/IGF-1 axis by CJC-1295, a long-acting GHRH analog, results in serum protein profile changes in normal adult subjects.",
      "doi": "10.1016/j.ghir.2009.03.001",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19386527/",
      "interpretation": "A CJC cohort subset adds serum-proteomic markers, not independent functional replication."
    },
    {
      "pmid": "19174493",
      "year": "2009",
      "title": "Effects of an oral growth hormone secretagogue in older adults.",
      "doi": "10.1210/jc.2008-0632",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19174493/",
      "interpretation": "Capromorelin shows selected older-adult functional outcomes in a different drug and predefined limitation setting."
    },
    {
      "pmid": "20439575",
      "year": "2010",
      "title": "The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial.",
      "doi": "10.7326/0003-4819-152-9-201005040-00007",
      "url": "https://pubmed.ncbi.nlm.nih.gov/20439575/",
      "interpretation": "A blinded athlete study retains a real sprint positive, with null other performance endpoints and loss after washout."
    },
    {
      "pmid": "23636184",
      "year": "2013",
      "title": "Human growth hormone may be detrimental when used to accelerate recovery from acute tendon-bone interface injuries.",
      "doi": "10.2106/JBJS.L.00222",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23636184/",
      "interpretation": "GH rat tendon-bone repair is null in one protocol and mechanically worse in prolonged high-dose exposure."
    },
    {
      "pmid": "25331030",
      "year": "2014",
      "title": "Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients.",
      "doi": "10.1007/s00384-014-2030-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25331030/",
      "interpretation": "Human postoperative ipamorelin does not improve its key meal-tolerance endpoint despite rodent motility support."
    },
    {
      "pmid": "25038357",
      "year": "2014 Jul 23-30",
      "title": "Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial.",
      "doi": "10.1001/jama.2014.8334",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25038357/",
      "interpretation": "Tesamorelin improves adiposity endpoints in HIV-related disease with explicit metabolic monitoring."
    },
    {
      "pmid": "26906526",
      "year": "2016",
      "title": "Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials.",
      "doi": "10.1016/S1470-2045(15)00558-6",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26906526/",
      "interpretation": "Two ROMANA trials show lean-mass gains without co-primary handgrip improvement in cancer cachexia."
    },
    {
      "pmid": "42542926",
      "year": "2026",
      "title": "Effects of BPC-157 and TB-500 on Achilles tendon healing in rats: A histopathological and biomechanical study.",
      "doi": "10.52312/jdrs.2026.2951",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42542926/",
      "interpretation": "A recent BPC-157/TB-500 rat component comparison finds no added combination benefit, reinforcing molecule-specific testing."
    }
  ],
  "gaps": [
    "Direct human functional outcomes for the exact combination.",
    "Formulation equivalence between long-acting albumin-binding CJC-1295 and products sold under similar names.",
    "Component-dismantling evidence and patient-relevant synergy rather than hormone synergy.",
    "Adequately powered functional endpoints and distinction between contractile tissue, fluid, appetite and measured recovery.",
    "Longer-term controlled safety and net benefit under verified product exposure.",
    "Translation of full-length thymosinbeta4 and newer TB-500 animal mechanical results to defined human indications without treating different peptides as one class."
  ],
  "decisive_experiment": "A preregistered blinded factorial comparison of formulation-verified CJC-1295, ipamorelin, their exact combination and placebo in a predefined adult recovery setting without diagnosed GH deficiency, with matched rehabilitation and an independently assessed functional recovery endpoint over4–24 weeks."
}