Dienogest

證據等級: L5

預測適應症: 10 個

Dienogest: From Endometriosis to Amenorrhea

One-Sentence Summary

Dienogest is a fourth-generation selective progestin widely used for the treatment of endometriosis, acting by suppressing the hypothalamic-pituitary-ovarian (HPO) axis to reduce estrogen-driven ectopic endometrial growth. The TxGNN model predicts it may be effective for Amenorrhea, with 4 clinical trials and 6 publications currently retrieved — however, mechanistic analysis reveals this is almost certainly a contra-directional prediction: Dienogest induces amenorrhea as a deliberate therapeutic effect in endometriosis management, rather than treating primary amenorrhea as a condition.

Quick Overview

Item	Content
Original Indication	Endometriosis (known standard clinical use; no CBG-MEB marketing authorization on record for the Netherlands)
Predicted New Indication	Amenorrhea
TxGNN Prediction Score	99.71%
Evidence Level	L3
NL Market Status	Not marketed in the Netherlands
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in the provided evidence pack. Based on established pharmacological knowledge, Dienogest is a fourth-generation synthetic progestin with highly selective progesterone receptor agonist activity and minimal androgenic, estrogenic, or glucocorticoid effects. It treats endometriosis by suppressing the HPO axis: inhibiting ovulation and follicular maturation, lowering endogenous estradiol concentrations, and inducing endometrial decidualization and atrophy — with amenorrhea being a direct and intended therapeutic outcome.

This is precisely where the mechanistic paradox lies. Amenorrhea is not a condition that Dienogest is designed to treat — it is a condition that Dienogest causes, intentionally, as a cornerstone of its efficacy against ectopic endometrial tissue. Prescribing Dienogest to treat primary or secondary amenorrhea in a patient who already lacks menstruation would be pharmacologically contradictory and could worsen underlying hormonal suppression.

The TxGNN model has likely captured the statistical co-occurrence of Dienogest, endometriosis, and amenorrhea in the knowledge graph without distinguishing the causal direction of the relationship. This is a recognized limitation of graph-based repurposing models: they can identify strongly associated node pairs without inferring whether the drug causes, treats, or simply correlates with the disease. This prediction should be classified as a contra-directional artifact, not a genuine repurposing opportunity, and may be worth flagging as a pipeline quality signal.

Clinical Trial Evidence

Important context: All retrieved clinical trials pertain to Dienogest’s established endometriosis indication, not to treating amenorrhea. Amenorrhea in these trials appears as an outcome measure or adverse event — not as the therapeutic target. No trials treating amenorrhea with Dienogest were identified.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT07164183	Phase 3	Recruiting	290	Non-inferiority RCT comparing Indinol Forto® 200 mg vs Visanne® (Dienogest 2 mg) for endometriosis; amenorrhea rate likely a secondary outcome
NCT02425462	N/A	Completed	895	Large prospective observational cohort assessing Visanne® effectiveness and long-term safety for quality of life in Asian women with endometriosis across routine clinical settings
NCT04495855	N/A	Completed	968	Real-world observational study of Dienogest in endometriosis; evaluates symptom control, recurrence after treatment cessation, and tolerability profile
NCT07204093	N/A	Active, not recruiting	138	Comparison of Dienogest vs drospirenone combined with transdermal estradiol in endometriosis; evaluates patient satisfaction and tolerability

Literature Evidence

PMID	Year	Type	Journal	Key Findings
39090694	2024	Systematic Review	BMC Pharmacology & Toxicology	Bayesian analysis of Dienogest adverse effects across multiple studies; identifies irregular bleeding and amenorrhea as frequent outcomes — confirming amenorrhea as an effect of the drug, not a treated condition
34405378	2022	Narrative Review	Reviews in Endocrine & Metabolic Disorders	Overview of hormonal endometriosis treatments; describes estrogen-dependency and progesterone-resistance as key pathogenic events; covers Dienogest’s HPO axis suppression mechanism
41329046	2026	Pharmacological Study	European Journal of Contraception & Reproductive Health Care	Quantitative pharmacological analysis of Dienogest 2 mg inhibition ratio; amenorrhea induction explicitly described as a mechanism of therapeutic action in endometriosis
29161960	2018	Prospective Cohort	Reproductive Sciences	Retrospective cohort of 514 women with ovarian endometrioma across 7 hospitals; evaluates long-term efficacy and safety of Dienogest beyond 12 months including recurrence rates
34918698	2021	Case Report	Medicine	Ovarian granulosa cell tumor in a PCOS patient; minimal direct relevance to Dienogest or amenorrhea as a treatment target
40543564	2025	Review/Imaging	Journal of Pediatric and Adolescent Gynecology	Advanced 3D visualization techniques for obstructive Müllerian anomalies; minimal direct relevance to Dienogest repurposing

Netherlands Market Information

Dienogest currently holds no marketing authorization from the CBG-MEB (College ter Beoordeling van Geneesmiddelen) in the Netherlands. No RVG numbers are on record.

Dienogest is marketed as Visanne® 2 mg in multiple EU member states (approved via national procedures and EMA scientific opinion), as well as in Japan, South Korea, and Australia. Any use in the Netherlands would require either a new CBG-MEB marketing authorization application, an EMA centralized procedure submission, or a compassionate use (named patient) pathway under Dutch medicines law.

Safety Considerations

Please refer to the SmPC (Samenvatting van de Productkenmerken) for complete safety information. No warnings, contraindications, or drug interaction data were available in the current evidence pack.

For orientation: based on EMA public assessment reports for Visanne® in other EU member states, the known safety profile of Dienogest includes irregular uterine bleeding, headache, depressed mood, decreased libido, acne, weight gain, and potential impact on bone mineral density with prolonged use. Use during pregnancy and in patients with undiagnosed abnormal vaginal bleeding is contraindicated per the originator SmPC.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN prediction for amenorrhea is assessed as a contra-directional model artifact — Dienogest pharmacologically induces amenorrhea as part of its endometriosis mechanism, and no clinical evidence exists for its use as a treatment for primary or secondary amenorrhea. Proceeding with this indication as a repurposing candidate would be pharmacologically unjustified based on current evidence.

To proceed, the following is needed:

Mandatory: Clinical pharmacologist review to formally confirm the contra-directional classification and close this candidate in the pipeline
Pipeline quality action: Flag this prediction pair (Dienogest ↔ Amenorrhea) as a known model artifact for the NlTxGNN contra-directional prediction audit
For completeness: Extract the full MOA profile from DrugBank (DB09123) and EMA SmPC to document for future similar progestin candidates
If any amenorrhea subtype warrants further review (e.g., progestin challenge testing in evaluation of amenorrhea etiology), a separate, narrowly scoped clinical question should be formulated with a gynecologist before re-evaluation
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.