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 progestin widely used for endometriosis treatment, exerting its effects through progesterone receptor agonism and suppression of the hypothalamic–pituitary–gonadal (HPG) axis.

The TxGNN model predicts it may be effective for Amenorrhea, with 4 clinical trials and 6 publications currently associated with this direction — however, a critical interpretive caveat applies: amenorrhea in this context is a well-documented pharmacological side effect of dienogest (occurring in 50–70% of users), not an established therapeutic target, suggesting the model may have captured a reversed causal relationship.

Quick Overview

Item	Content
Original Indication	Endometriosis (established from clinical trial and literature context; no Saudi Arabia registration)
Predicted New Indication	Amenorrhea
TxGNN Prediction Score	99.71%
Evidence Level	L3
Saudi Arabia Market Status	Not marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Dienogest acts as a selective progesterone receptor agonist with high oral bioavailability and minimal androgenic activity. Its primary mechanism involves suppression of the HPG axis — reducing LH and FSH secretion, lowering circulating estrogen, and directly inhibiting ectopic endometrial cell proliferation and survival. This makes it highly effective for endometriosis-associated pain and lesion control.

As a direct consequence of this HPG suppression, dienogest reliably induces amenorrhea in a substantial proportion of treated women. The 2026 mechanistic study (PMID 41329046) explicitly states that "inducing amenorrhoea and a hypoestrogenic environment" is the intended therapeutic objective of dienogest in endometriosis — confirming that amenorrhea is the pharmacological mechanism, not the target indication. TxGNN's biological knowledge graph almost certainly captured this strong co-occurrence between dienogest and amenorrhea and scored it as a repurposing signal.

Critically, the causal direction is reversed from a repurposing standpoint. Treating primary amenorrhea (hypothalamic, pituitary, or structural origin) or secondary amenorrhea with additional HPG suppression would be pharmacologically counterproductive in most etiologies. A narrow diagnostic use case exists — the progesterone challenge test for assessing estrogen priming in secondary amenorrhea workup — but this is a diagnostic tool, not a therapeutic indication. Before any further development consideration, the specific amenorrhea subtype and clinical context must be defined.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT04495855	N/A	Completed	968	Real-world observational study of dienogest (Visanne) for endometriosis in routine clinical practice; amenorrhea tracked as a secondary safety endpoint, reflecting a known side effect rather than a therapeutic target
NCT02425462	N/A	Completed	895	Prospective cohort study in Asian women with endometriosis assessing quality-of-life improvement and long-term safety; amenorrhea rate reported as a tolerability finding
NCT07164183	Phase 3	Recruiting	290	Non-inferiority Phase 3 trial comparing Indinol Forto® 200 mg vs. Visanne 2 mg for endometriosis treatment; amenorrhea not a primary endpoint
NCT07204093	N/A	Active, not recruiting	138	Comparison of transdermal estradiol add-back with dienogest vs. drospirenone for bone protection in endometriosis; designed to mitigate dienogest-induced hypoestrogenism, not to treat amenorrhea

Important: All 4 identified trials target endometriosis as the primary indication. Amenorrhea appears exclusively as a secondary safety or tolerability endpoint — reflecting a drug-induced side effect — in none of these trials is amenorrhea the therapeutic target being treated.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
39090694	2024	Systematic Review / Meta-analysis	BMC Pharmacology & Toxicology	Bayesian analysis of dienogest adverse effects; irregular bleeding and amenorrhea confirmed as among the most prevalent adverse events, quantifying their pharmacological — not therapeutic — role
34405378	2022	Narrative Review	Reviews in Endocrine & Metabolic Disorders	Comprehensive review of hormonal treatments for endometriosis; frames estrogen dependency and progesterone resistance as the core disease drivers, providing mechanistic context for dienogest's HPG suppression strategy
41329046	2026	Clinical / Mechanistic Study	European Journal of Contraception & Reproductive Health Care	Demonstrates high inhibition ratio and transformation index for 2 mg dienogest; explicitly identifies inducing amenorrhea and a hypoestrogenic environment as the treatment objective in endometriosis, confirming reversed causation relative to the TxGNN prediction
29161960	2018	Cohort Study	Reproductive Sciences	Retrospective cohort of 514 women with ovarian endometrioma on long-term dienogest (>12 months); amenorrhea and breakthrough bleeding patterns documented as key long-term tolerability outcomes
34918698	2021	Case Report	Medicine	Case report of ovarian granulosa cell tumor in a PCOS patient; tangential association with amenorrhea context, no direct relevance to dienogest repurposing
40543564	2025	Review	Journal of Pediatric and Adolescent Gynecology	Advanced visualization for Müllerian anomalies; relevant as obstructive anomalies are a structural cause of primary amenorrhea — where hormonal therapy such as dienogest would have no role

Saudi Arabia Market Information

Dienogest currently has no approved product registrations with the Saudi Food and Drug Authority (SFDA). No marketed formulations exist in Saudi Arabia at this time, and accordingly no authorized indication data is available.

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN model has identified a pharmacologically real — but directionally reversed — association: dienogest reliably induces amenorrhea as a high-incidence side effect (50–70%) through HPG axis suppression, rather than serving as a treatment for amenorrhea as a primary disease state. All 4 clinical trials and the 6 publications identified support the endometriosis indication, with amenorrhea appearing only as a secondary safety endpoint. There is no clinical trial or literature evidence supporting dienogest as a therapeutic agent for primary or secondary amenorrhea of other etiologies, and pharmacological reasoning suggests it would be counterproductive in most amenorrhea subtypes.

To proceed, the following is needed:

Formal clarification of the clinical question: is there a specific amenorrhea subtype (e.g., progesterone challenge test in secondary amenorrhea diagnosis) where dienogest's HPG-suppressive effect could be used constructively?
SFDA product registration and local package insert retrieval to complete safety evaluation (currently a blocking data gap)
MOA documentation from DrugBank to support mechanistic plausibility analysis
If the primary endometriosis indication is pursued first (as recommended), the amenorrhea repurposing signal can be reconsidered in the context of any future indication expansion after market entry is established
Disclaimer

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