Dienogest

證據等級: L5

預測適應症: 10 個

Dienogest: From Endometriosis to Amenorrhea

One-Sentence Summary

Dienogest (Visanne®) is a fourth-generation progestin established for the treatment of endometriosis, where it suppresses the hypothalamic-pituitary-ovarian (HPO) axis to reduce estrogen and control ectopic endometrial tissue. The TxGNN model predicts it may be applicable to Amenorrhea, with 4 clinical trials and 6 publications currently available — however, all existing evidence documents amenorrhea as a pharmacological consequence of dienogest therapy (incidence 40–70%), not as a primary therapeutic target. This mechanistic inversion is the central issue: the drug induces amenorrhea rather than treats it, and the research question must be carefully re-framed before any repurposing pathway can be defined.

Quick Overview

Item	Content
Original Indication	Endometriosis
Predicted New Indication	Amenorrhea (disease)
TxGNN Prediction Score	99.71%
Evidence Level	L3
Singapore Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Dienogest is a fourth-generation synthetic progestin with highly selective progesterone receptor (PR-A and PR-B) affinity and minimal androgenic or estrogenic activity. Its primary mechanism in endometriosis is suppression of the HPO axis, which reduces circulating estradiol to early follicular-phase levels, depriving ectopic endometrial implants of hormonal stimulation. A direct pharmacological consequence of this HPO suppression is the reliable induction of amenorrhea, reported in 40–70% of patients across clinical studies.

The TxGNN model almost certainly detected the strong statistical co-occurrence between dienogest and amenorrhea in the biomedical knowledge graph — a correlation that is pharmacologically valid, but reflects a causal rather than therapeutic relationship. Pathological amenorrhea (e.g., hypothalamic amenorrhea, PCOS-related anovulation, or structural causes) requires restoration of normal hormonal cycling, not further suppression. Administering a potent HPO-suppressing progestin to treat amenorrhea would, in most disease contexts, worsen rather than resolve the condition.

That said, a legitimate re-framing exists: where therapeutic amenorrhea is the intended clinical goal — such as managing refractory heavy menstrual bleeding, relieving endometriosis-related dysmenorrhea, or providing hormonal quiescence prior to uterine procedures — dienogest's amenorrhea-inducing property could reasonably be considered its primary therapeutic mechanism. Pursuing this angle, however, requires a distinctly defined research question separate from "treating amenorrhea disease."

Clinical Trial Evidence

Important context: All four identified trials target endometriosis as the primary indication. Amenorrhea appears in these trials as a secondary endpoint or a documented adverse event — not as the condition being treated.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT07164183	Phase 3	Recruiting	290	Multicenter non-inferiority RCT comparing Indinol Forto® 200 mg vs Visanne® 2 mg in endometriosis; amenorrhea rate likely captured as a secondary efficacy or safety endpoint
NCT02425462	Observational	Completed	895	ENVISION prospective cohort in Asian women with endometriosis treated with dienogest in routine practice; amenorrhea recorded as an adverse event rather than a treatment outcome
NCT04495855	Observational	Completed	968	VISANNE real-world study in endometriosis; provides real-world incidence data on amenorrhea during dienogest therapy
NCT07204093	Observational	Active, Not Recruiting	138	Compares dienogest+transdermal estradiol versus drospirenone+transdermal estradiol regimens in endometriosis; focuses on patient satisfaction and tolerability

Literature Evidence

PMID	Year	Type	Journal	Key Findings
39090694	2024	Systematic Review + Bayesian Analysis	BMC Pharmacology & Toxicology	Comprehensive adverse effect profile of dienogest across endometriosis and adenomyosis studies; amenorrhea is among the most frequently reported pharmacological effects
41329046	2026	Mechanistic/Pharmacological Study	Eur J Contracept Reprod Health Care	Characterises the high inhibition ratio and transformation index of 2 mg dienogest; explicitly frames amenorrhea induction and hypoestrogenic environment as the intended therapeutic mechanism in endometriosis
34405378	2022	Narrative Review	Reviews in Endocrine & Metabolic Disorders	Endocrine basis of hormonal endometriosis therapy; covers progesterone resistance, estrogen dependency, and long-term hormonal management strategies
29161960	2018	Retrospective Cohort	Reproductive Sciences	Long-term efficacy and safety of dienogest in 514 women with ovarian endometrioma over >12 months; documents sustained amenorrhea rates and recurrence patterns

Singapore Market Information

Dienogest is not currently registered or marketed in Singapore. No product authorizations are on record with HSA. Brands available in neighbouring markets (e.g., Visanne® by Bayer) would require a separate registration application before any clinical use in Singapore.

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN prediction captures a real pharmacological relationship — dienogest reliably induces amenorrhea — but the mechanistic direction is inverted relative to a repurposing claim. All available clinical trial and literature evidence positions amenorrhea as a downstream effect of HPO suppression in endometriosis management, not as a disease being treated. Without first resolving whether the target indication is "therapeutic amenorrhea induction" (plausible) or "treatment of pathological amenorrhea" (contradicted by mechanism), this candidate cannot advance to safety or feasibility review.

To proceed, the following is needed:

Re-define the research question: Clarify whether the proposed repurposing is (a) using dienogest's amenorrhea-inducing property as a primary endpoint in a new indication such as heavy menstrual bleeding or pre-procedural hormonal quiescence, or (b) treating pathological amenorrhea — the latter lacks mechanistic support and should be deprioritised
Retrieve complete MOA data from DrugBank (currently unavailable) to confirm receptor binding profile, HPO suppression kinetics, and tissue selectivity
Obtain full safety profile from the package insert or an HSA-equivalent monograph (all key warnings and contraindications are currently missing — a blocking data gap)
Assess Singapore registration pathway: With zero existing authorizations and no HSA-approved product, a fresh regulatory strategy is required before any clinical development can be planned locally
If pursuing therapeutic amenorrhea induction: Design a prospective study with amenorrhea rate as the primary endpoint and clinically meaningful secondary endpoints (e.g., pain scores, quality of life) to distinguish this from existing endometriosis indications

This report is generated for research reference purposes only and does not constitute medical advice. All repurposing candidates require clinical validation before any therapeutic application.

Disclaimer

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