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 synthetic progestin with established clinical use for endometriosis in numerous countries outside Denmark. The TxGNN model predicts it may be effective for Amenorrhea, with 4 clinical trials and 6 publications retrieved in relation to this direction. ⚠️ However, a critical mechanistic contradiction is identified: dienogest’s core pharmacological action actively induces amenorrhoea as a therapeutic endpoint — strongly suggesting this high-scoring prediction is an algorithmic false positive rather than a genuine repurposing opportunity.

Quick Overview

Item	Content
Original Indication	Endometriosis (inferred from clinical context and trial data; no Danish marketing authorisation on record)
Predicted New Indication	Amenorrhea (disease)
TxGNN Prediction Score	99.71%
Evidence Level	L3
Denmark Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

⚠️ Mechanistic Contradiction Warning — Likely Algorithmic False Positive

Detailed mechanism of action data is not available from DrugBank for this assessment. However, based on established pharmacology, dienogest is a fourth-generation progestin with highly selective progesterone receptor agonist activity and no oestrogenic activity. Its core mechanism for treating endometriosis involves suppressing LH pulsatile secretion, reducing ovarian oestradiol production, and inducing endometrial atrophy via the hypothalamic-pituitary-ovarian (HPO) axis. Clinically, the amenorrhoea rate serves as a primary efficacy endpoint in endometriosis trials — amenorrhoea is the intended pharmacological consequence of treatment, not a disease state that dienogest is designed to reverse.

Positioning dienogest as a treatment for amenorrhoea (disease) therefore creates a fundamental mechanistic contradiction: the drug causes amenorrhoea; it does not treat it. The TxGNN high prediction score (0.9971) most plausibly arises from dense knowledge graph connectivity between dienogest, the HPO axis, and menstrual cycle nodes — a well-recognised source of non-specific, false-positive scoring in graph-based models.

The only theoretically indirect link would involve evaluation of menstrual recovery after cessation of dienogest in women with endometriosis-related secondary menstrual dysfunction. However, this represents a post-treatment pharmacokinetic observation, not a direct therapeutic mechanism targeting amenorrhoea as a primary condition. No clinical programme has been designed around this hypothesis.

Clinical Trial Evidence

All retrieved trials enrolled endometriosis patients. Amenorrhoea appears in these studies exclusively as a reported side effect, tolerability endpoint, or as a baseline pharmacological condition intentionally induced by dienogest — not as the target disease.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT07164183	Phase 3	Recruiting	290	Multicenter open-label RCT comparing Indinol Forto® 200 mg vs Visanne® 2 mg (dienogest) for endometriosis; non-inferiority design; amenorrhoea likely captured as a tolerability measure
NCT02425462	N/A (Observational)	Completed	895	Prospective observational cohort of Visanne® in Asian women with endometriosis across routine clinical settings; quality of life as primary endpoint; amenorrhoea rate documented as secondary safety/tolerability item
NCT04495855	N/A (Observational)	Completed	968	Real-world observational study of dienogest in endometriosis clinical practice; evaluated symptom control and long-term treatment outcomes; amenorrhoea recorded as a common adverse event
NCT07204093	N/A	Active, not recruiting	138	Compares transdermal oestradiol add-back (with dienogest vs drospirenone) in endometriosis; study design explicitly presupposes dienogest-induced amenorrhoea as the pharmacological baseline state, then adds oestradiol to mitigate hypoestrogenic side effects — this further confirms dienogest as an amenorrhoea inducer, not a treatment

Literature Evidence

PMID	Year	Type	Journal	Key Findings
39090694	2024	Systematic Review + Bayesian Analysis	BMC Pharmacology & Toxicology	Comprehensive analysis of adverse effects of dienogest in endometriosis and adenomyosis; amenorrhoea confirmed as the predominant reported pharmacological effect, consistent with its mechanism of action
34405378	2022	Narrative Review	Reviews in Endocrine & Metabolic Disorders	Reviews hormonal management of endometriosis; confirms oestrogen dependency and progesterone resistance as key pathogenic factors; describes HPO axis suppression by dienogest as the central therapeutic mechanism
41329046	2026	Pharmacological / Mechanistic Study	European Journal of Contraception & Reproductive Health Care	Demonstrates high inhibition ratio and transformation index of dienogest 2 mg; supports induction of amenorrhoea and a hypoestrogenic milieu as the intended pharmacological goal in endometriosis management
29161960	2018	Retrospective Cohort	Reproductive Sciences	Long-term efficacy and safety of dienogest in ovarian endometrioma (N=514, 7 university hospitals); amenorrhoea rate and endometrioma recurrence evaluated as key outcomes at >12 months of treatment
34918698	2021	Case Report	Medicine	Case report of ovarian granulosa cell tumour in a PCOS patient; tangentially related to ovarian hormone physiology but provides no evidence for dienogest use in amenorrhoea
40543564	2025	Review / Imaging Study	Journal of Pediatric and Adolescent Gynecology	Advanced 3D and VR visualisation techniques for Müllerian anomalies; addresses structural causes of amenorrhoea but contains no data relevant to dienogest as a pharmacological intervention

Denmark Market Information

Dienogest is currently not authorised for sale in Denmark. No marketing authorisations have been registered with the Danish Medicines Agency (Lægemiddelstyrelsen), and the product has no market presence.

For reference, dienogest (as Visanne® 2 mg tablets, Bayer AG) holds marketing authorisation in Germany and multiple other EU member states, and has been approved for endometriosis in Japan, South Korea, and Australia, among others. Any use in Denmark would currently require a named-patient or compassionate use application to Lægemiddelstyrelsen.

Safety Considerations

Please refer to the approved Summary of Product Characteristics (SmPC) — for example, the German or EMA-registered Visanne® SmPC — for full safety information.

Warnings, contraindications, and drug interaction data specific to the Danish regulatory context were not available for this assessment. Clinicians should note that progestins as a class carry class-specific considerations including thromboembolic risk in relevant patient populations, effects on bone mineral density with prolonged use, and potential mood-related adverse effects.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN prediction of amenorrhoea as a new indication for dienogest is assessed as a high-confidence algorithmic false positive. Dienogest’s established pharmacological mechanism causes amenorrhoea as a therapeutic outcome in endometriosis management; there is no biological or clinical basis for its use as a treatment for amenorrhoea as a primary disease. All four retrieved clinical trials and the most directly relevant literature confirm this reverse relationship. The prediction score likely reflects non-specific HPO-axis network connectivity in the TxGNN knowledge graph rather than a genuine drug–disease therapeutic relationship.

To proceed, the following is needed:

Mechanistic clarification: Define whether any specific amenorrhoea subtype exists (e.g., anovulatory amenorrhoea secondary to chronic oestrogen excess) where progestogenic activity could theoretically restore cycling — and confirm this is distinct from dienogest’s suppressive mechanism
MOA data retrieval: Obtain complete DrugBank MOA entry for dienogest, including progesterone receptor subtype (PRA/PRB) selectivity and downstream endometrial signalling data
Safety data retrieval: Download and parse the Visanne® SmPC (Bayer AG) or the TFDA package insert to complete the safety profiling, including contraindications and key warnings
Targeted literature search: Conduct a focused PubMed search for progestin therapy specifically indicated for amenorrhoea treatment (not endometriosis management) to identify any precedent
False positive flagging: Consider categorising this prediction as a graph-artifact false positive in the TxGNN output pipeline to prevent recurrence in future runs; the amenorrhoea–progestin node connection should be annotated with directionality (drug induces condition, not treats it)

This report is generated for research purposes only and does not constitute medical advice. All drug repurposing candidates require prospective clinical validation before any therapeutic application. Data cutoff: 2026-04-05.

Disclaimer

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