Prohormone: Physiology and What Research Reports

What a prohormone is

In physiology, a prohormone is a larger precursor protein that a cell makes first and then cuts into one or more smaller peptides that carry the actual signalling activity. The precursor is translated from a single gene, folded in the endoplasmic reticulum, sorted into the secretory pathway, and trimmed by specific enzymes before release. Familiar examples include proinsulin, which yields insulin and C-peptide, and proglucagon, which yields different products depending on which cell type processes it.

Two features define the concept. First, one gene can give rise to several distinct peptides, so the final signal depends on which enzymes a cell expresses, not only on which gene is switched on. Second, the precursor sequence contains cleavage sites — often pairs of basic amino acids — that mark where the cuts occur. Researchers who study prohormone processing in human enteroendocrine cells used genetically engineered organoid models to map which proteases act on which sites, an approach reported in 2022.

Two very different uses of the same word

Readers meet "prohormone" in two unrelated contexts, and conflating them causes confusion.

The supplement category was surveyed in a 2006 review of testosterone prohormone supplements in Medicine & Science in Sports & Exercise, which examined the hormonal and safety questions raised by these products in the published literature. The rest of this page concerns the physiological sense, because that is the meaning used throughout peptide science.

Where prohormones are produced and processed

Prohormone processing happens along the regulated secretory pathway of endocrine cells, neurons, and gut enteroendocrine cells. After the signal peptide is removed, the prohormone travels to the Golgi and into dense-core secretory granules, where prohormone convertases (notably PC1/3 and PC2) and carboxypeptidases perform the cuts in the acidic, calcium-rich granule environment.

Quality control before that step matters too. A study of islet α cells described how the SEL1L-HRD1 endoplasmic-reticulum-associated degradation pathway facilitated prohormone convertase 2 maturation and glucagon production, as the authors reported in Nature Communications. The conformation of the precursor itself is also part of the story: researchers examining pro-islet amyloid polypeptide in micelles found the molecule contained a helical prohormone segment, described in The FEBS Journal.

Prohormones as more than passive precursors

Some precursors do work of their own. One study characterised the prohormone VGF as a regulator of β cell function through insulin secretory granule biogenesis, an effect the investigators reported in Cell Reports. Outside animals, a plant prohormone called prosystemin, which modulates plant defence barriers, was shown to be an intrinsically disordered protein in work published in Protein Science — evidence that the prohormone strategy is not limited to vertebrate endocrinology.

How prohormones are identified and measured

Because prohormone-derived peptides are short, low in abundance, and poorly conserved in sequence, they are hard to find by classical methods. Several complementary approaches appear in the literature.

• Bioinformatic prediction. Methods chapters have laid out workflows for prohormone and neuropeptide discovery from genome and transcriptome data, including cleavage-site prediction and homology searching, as summarised in Methods in Molecular Biology.
• Comparative and evolutionary genomics. A survey of neuropeptide prohormone genes across Cetartiodactyla livestock and wild species examined changes associated with evolution and domestication, reported in Veterinary Sciences, while a separate chapter applied prohormone discovery to basal metazoans using Trichoplax as the model system.
• Engineered human tissue models. The enteroendocrine organoid work mapped protease-specific contributions to prohormone cleavage in human cells rather than inferring them from rodents in the reported experiments.
• Prohormone ratios as biomarkers. Investigators studying auto-islet transplant recipients evaluated elevated islet prohormone ratios — unprocessed precursor relative to mature hormone — as indicators of insulin dependency, reported in the American Journal of Transplantation.

Why the term matters in peptide research

Most of the well-known signalling peptides studied today are prohormone fragments, so the processing step determines which molecules actually exist in tissue. That makes precursor sequences a search space for undiscovered peptides. A 2025 Nature paper applied prohormone cleavage prediction and, in doing so, uncovered a non-incretin anti-obesity peptide, as the authors reported in that study. The wider point for readers is conceptual: a peptide's identity, length, and activity depend on where the precursor was cut, and the same gene can produce different peptides in different cell types.

Prohormone processing and disease: What Studies Report

When processing fails, unprocessed precursors accumulate and mature signals are lost. A review in the Journal of Clinical Investigation proposed impaired prohormone processing as a possible unifying explanation for features of Prader-Willi syndrome, a hypothesis the authors set out in that article. In transplantation, the elevated prohormone ratios described above were examined in relation to insulin dependency after auto-islet transplantation in the reported cohort, and the α-cell work connected an ER quality-control pathway to convertase maturation and glucagon output in that study.

Supplement "prohormones": What Studies Report

The sports-supplement category shares only the name. A 2006 review examined testosterone prohormone supplements and the questions surrounding their hormonal effects and safety, published in Medicine & Science in Sports & Exercise. No dosing figures are reproduced here, because the verified literature summarised on this page does not supply them, and readers who encounter such products in commercial settings should note that the regulatory status of these compounds differs by country and product. This page is for educational purposes only and is not medical advice; consult a licensed physician about any medical question, symptom, or product.

Key takeaways

1. A prohormone is a precursor protein cleaved into active peptides; the cleavage pattern, not just the gene, defines the final signal as mapped in human enteroendocrine organoids.
2. Processing enzymes and ER quality-control pathways are themselves regulated, as researchers reported for prohormone convertase 2 in α cells.
3. Prohormone sequences remain a source of newly described peptides, illustrated by the cleavage-prediction study published in Nature in 2025.

References

• Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide (Nature, 2025)
• Bioinformatics for Prohormone and Neuropeptide Discovery (Methods in Molecular Biology, 2024)
• Bioinformatic Prohormone Discovery in Basal Metazoans: Insights from Trichoplax (Methods in Molecular Biology, 2024)
• SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells (Nature Communications, 2026)
• Mapping prohormone processing by proteases in human enteroendocrine cells using genetically engineered organoid models (PNAS, 2022)
• Changes in Neuropeptide Prohormone Genes among Cetartiodactyla Livestock and Wild Species Associated with Evolution and Domestication (Veterinary Sciences, 2022)
• The Prohormone VGF Regulates β Cell Function via Insulin Secretory Granule Biogenesis (Cell Reports, 2017)
• Impaired prohormone processing: a grand unified theory for features of Prader-Willi syndrome? (The Journal of Clinical Investigation, 2017)
• Prosystemin, a prohormone that modulates plant defense barriers, is an intrinsically disordered protein (Protein Science, 2018)
• Pro-islet amyloid polypeptide in micelles contains a helical prohormone segment (The FEBS Journal, 2020)
• Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients (American Journal of Transplantation, 2022)
• Testosterone prohormone supplements (Medicine and Science in Sports and Exercise, 2006)