Women with PCOS showed significantly higher kisspeptin-to-dynorphin ratios due to reduced dynorphin expression, suggesting this neuropeptide imbalance may drive the hormonal disruptions characteristic of the condition.
KISS1/PDYN ratio significantly elevated in PCOS (p=0.02)Driven by reduced dynorphin (the brake peptide), not increased kisspeptin — suggesting the 'stop' signal for reproductive hormones is weakened in PCOS
What the researchers found
The KISS1/PDYN (kisspeptin/prodynorphin) ratio was significantly higher in PCOS women compared to controls (p=0.02). Prodynorphin expression was significantly lower in the PCOS group (p<0.001). The positive correlation between KISS1 expression and the KISS1/PDYN ratio was much stronger in PCOS women (R=0.93, p<0.001) than controls (R=0.66, p<0.001).
The authors conclude that diminished dynorphin expression — not elevated kisspeptin alone — drives the increased ratio, and that this imbalance is highly specific to PCOS.
Why it matters
PCOS is the most common endocrine disorder in women of reproductive age, causing irregular periods, infertility, and metabolic problems. Understanding that dynorphin deficiency creates a neuropeptide imbalance could point toward new treatment approaches — potentially using drugs that boost dynorphin signaling or dampen kisspeptin to restore normal reproductive hormone pulsing.
How the study worked
Cross-sectional study of 20 women with PCOS and 20 without, enrolled at Cipto Mangunkusumo hospital in Jakarta, Indonesia (August–December 2022). Peripheral blood mRNA expression of KISS1, prodynorphin (PDYN), tachykinin-3 (neurokinin-B), leptin, and neuropeptide-Y was measured using quantitative PCR.
What this study cannot tell us
Small sample size of 40 total women. The study measured peripheral blood mRNA, which may not perfectly reflect hypothalamic neuropeptide expression. Cross-sectional design cannot establish causation. Conducted at a single center in Indonesia, which may limit generalizability across ethnic populations.
How to read the evidence
This is an observational cross-sectional study with a small sample size (40 women). It identifies an association between neuropeptide imbalance and PCOS but cannot prove causation.
When this study was published
Published in 2024, this is current research that provides human data supporting the KNDy neuron hypothesis in PCOS, which has been primarily based on animal studies.
The bigger picture
The KNDy neuron hypothesis (kisspeptin, neurokinin-B, dynorphin) proposes that these three neuropeptides together control GnRH pulse frequency. In PCOS, GnRH pulses are abnormally rapid, favoring LH over FSH and disrupting ovulation. This study provides human evidence supporting the theory that reduced dynorphin — the brake in the system — contributes to this dysregulation, complementing animal data that previously drove this hypothesis.
Questions still open
- Could drugs that enhance dynorphin signaling (kappa opioid receptor agonists) help restore normal GnRH pulsing in PCOS?
- Does the KISS1/PDYN ratio correlate with PCOS severity or specific phenotypes?
- Do peripheral blood neuropeptide mRNA levels reliably reflect what's happening in the hypothalamus?
Common questions
What do kisspeptin and dynorphin have to do with PCOS?
Could this finding lead to new PCOS treatments?
Read the original research
Altered expression of kisspeptin, dynorphin, and related neuropeptides in polycystic ovary syndrome: A cross-sectional study.
International journal of reproductive biomedicine, 22(5), 395-404
Citation
Hestiantoro, Andon; Noor Al Maghfira, Rachellina; Fathmasari, Ratna; Rahmala Febri, Ririn; Ongko Joyo, Ericko; Muharam, Raden; Pratama, Gita; Bowolaksono, Anom. (2024). Altered expression of kisspeptin, dynorphin, and related neuropeptides in polycystic ovary syndrome: A cross-sectional study.. International journal of reproductive biomedicine, 22(5), 395-404. https://doi.org/10.18502/ijrm.v22i5.16440