Cyproterone Acetate
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Cyproterone Acetate: From Antiandrogen Therapy to Amenorrhoea
One-Sentence Summary
Cyproterone acetate (CPA) is an antiandrogen and progestogen used internationally for conditions such as hirsutism, severe acne, and as a component of combined oral contraceptives. The TxGNN model predicts it may be effective for Amenorrhoea (particularly in the context of polycystic ovary syndrome), with 4 clinical trials and 14 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Antiandrogen therapy (hirsutism, acne, hyperandrogenism); not registered in South Africa |
| Predicted New Indication | Amenorrhoea |
| TxGNN Prediction Score | 99.28% |
| Evidence Level | L2 |
| South Africa Market Status | Not marketed |
| Number of SAHPRA Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Cyproterone acetate is a steroidal antiandrogen with potent progestogenic activity. It competitively blocks androgen receptors and suppresses gonadotropin secretion, thereby reducing circulating androgen levels. Internationally, it is most commonly used in combination with ethinyl oestradiol (as in Diane-35) for the treatment of androgen-dependent conditions such as severe hirsutism, acne, and seborrhoea in women.
Amenorrhoea is frequently a presenting symptom of polycystic ovary syndrome (PCOS), where hyperandrogenism disrupts normal ovulatory cycling. The combination of ethinyl oestradiol and cyproterone acetate (EE+CPA) addresses both the underlying androgen excess and the menstrual irregularity by (1) suppressing ovarian androgen production via gonadotropin inhibition, (2) directly blocking peripheral androgen receptors, and (3) providing cyclical progestogen withdrawal to restore predictable menstrual bleeding.
This prediction is strongly supported by existing clinical practice. EE+CPA-containing oral contraceptives are already widely prescribed for PCOS-related menstrual disorders in Europe, Asia, and parts of Africa. The TxGNN model has identified a genuine pharmacological relationship, making this one of the most clinically plausible predictions in this evaluation. However, CPA is not currently registered in South Africa, which would require importation via Section 21 application or new SAHPRA registration.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01103518 | Phase 4 | Unknown | 100 | Randomised double-blind comparative study of two EE+CPA preparations for menstrual irregularities of hyperandrogenic origin |
| NCT02729545 | Phase 2 | Completed | 60 | Tung’s acupuncture vs Diane-35 (CPA/EE) as control for improving ovarian function in PCOS; CPA served as active comparator |
| NCT02744131 | Not specified | Unknown | 100 | OCP containing CPA vs Metformin for improving clinical, hormonal, and metabolic features of PCOS in Indian women, including amenorrhoea management |
| NCT04831151 | Not specified | Unknown | 42 | Comparison of two OCPs (CPA-containing vs drospirenone-containing) on blood metabolomics in PCOS patients |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 2946604 | 1986 | Multicentre Trial | Fertil Steril | Low-dose (2 mg) vs high-dose (100 mg) CPA in 158 patients with severe hirsutism; both effective with similar outcomes |
| 9130733 | 1997 | Clinical Study | Hum Reprod | GnRH-a + EE/CPA vs EE/CPA alone in PCOD hyperandrogenism; EE/CPA effective for clinical and hormonal improvement |
| 2137793 | 1990 | Case Series | Fertil Steril | GnRH agonist + antiandrogen (CPA) reversed hirsutism and amenorrhoea in familial virilization with insulin resistance |
| 2528199 | 1989 | Review | Rev Fr Gynecol Obstet | CPA identified as the most effective antiandrogen for skin hyperandrogenism; must be combined with oestrogen to prevent amenorrhoea |
| 6232474 | 1984 | Review | Obstet Gynecol Annu | Overview of polycystic ovarian disease pathophysiology and management |
| 1589384 | 1992 | Case Report | Postgrad Med J | CPA used to treat secondary amenorrhoea and hirsutism in a patient with bilateral androgen-producing adrenal adenomas and PCOS |
| 35592826 | 2022 | Case Report | Ann Med Surg | Congenital adrenal hyperplasia (21-hydroxylase deficiency) presenting in adolescence; CPA relevant to hormonal management |
| 23365131 | 2013 | Case Report | J Clin Endocrinol Metab | Virilising sclerosing-stromal ovarian tumour in McCune-Albright syndrome; hormonal management context |
| 23221134 | 2012 | Clinical Study | Georgian Med News | EEG-guided pathogenetic management of central amenorrhoea in 159 infertile women compared to standard hormone therapy |
| 12266391 | 1984 | Clinical Study | J Bras Ginecol | Evaluation of a new ovulation inhibitor containing antiandrogen (CPA) |
South Africa Market Information
Cyproterone acetate is currently not registered with SAHPRA. There are no licensed products containing cyproterone acetate on the South African market.
Access pathways:
- Section 21 application to SAHPRA for unregistered medicines (individual patient or clinical trial basis)
- Products containing EE + CPA (e.g., Diane-35 equivalents) are available in many other African and European markets and could be sourced via parallel importation
Safety Considerations
Please refer to the SAHPRA-approved Professional Information (PI) for safety information. As CPA is not registered in South Africa, clinicians should consult international prescribing information (e.g., EMA SmPC or TGA PI). Report adverse drug reactions to SAHPRA.
Critical safety signals identified from the evidence review:
- Venous thromboembolism (VTE): CPA-containing oral contraceptives are associated with a higher risk of VTE compared to levonorgestrel-containing pills. This risk is synergistically increased in patients with Factor V Leiden mutation or other thrombophilias (PMID 29614525, 32342502).
- Prothrombotic effects: CPA increases activated protein C (APC) resistance, reduces protein S and antithrombin activity, and alters thrombin generation (PMID 15550051, 18064335).
- Hepatotoxicity: High-dose CPA (e.g., 100 mg for prostate cancer) is associated with hepatotoxicity including rare fatal hepatic failure; liver function monitoring is required.
- Meningioma risk: Prolonged use of CPA at doses ≥25 mg/day has been associated with an increased risk of meningioma (EMA safety review, 2020).
Other TxGNN Predictions: Critical Appraisal
The TxGNN model generated 10 predictions for cyproterone acetate. The table below summarises all predictions and highlights important safety concerns:
| Rank | Predicted Indication | Score | Evidence Level | Recommendation | Assessment |
|---|---|---|---|---|---|
| 1 | Migraine disorder | 99.66% | L4 | Hold | Indirect hormonal link; direction of effect uncertain |
| 2 | Migraine with brainstem aura | 99.58% | L5 | Hold | Contraindicated — CPA increases ischaemic stroke risk in migraine with aura |
| 3 | Prinzmetal angina | 99.52% | L5 | Hold | No mechanistic basis; likely false positive |
| 4 | Antithrombin deficiency type 2 | 99.48% | L5 | Hold | Reverse signal — CPA reduces antithrombin activity and worsens this condition |
| 5 | Heparin cofactor 2 deficiency | 99.45% | L5 | Hold | Reverse signal — CPA disrupts coagulation factor balance |
| 6 | Factor V excess with spontaneous thrombosis | 99.45% | L5 | Hold | Serious reverse signal — CPA synergistically increases VTE risk with Factor V abnormalities |
| 7 | Migraine susceptibility | 99.34% | L5 | Hold | Poor literature match; mostly epilepsy genetics studies |
| 8 | Amenorrhoea | 99.28% | L2 | Proceed with Guardrails | Strong positive signal — CPA/EE already used clinically for PCOS-related amenorrhoea |
| 9 | Breast fibrocystic disease | 99.15% | L5 | Hold | Theoretical only; no clinical evidence |
| 10 | Thrombophilia | 99.03% | L5 | Hold | Serious reverse signal — All 18 publications identify CPA as a thrombosis risk factor, not a treatment |
Key insight: Five of the 10 predictions (ranks 4, 5, 6, and 10, plus rank 2) represent conditions where CPA is a risk factor or contraindicated, not a potential treatment. This is a known limitation of graph-based prediction models — they detect strong associations but cannot distinguish causal direction (treatment vs. causation). Healthcare professionals must critically appraise all model predictions.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Cyproterone acetate (as part of EE+CPA combination) is already used internationally for PCOS-related menstrual disorders including amenorrhoea, supported by a Phase 4 post-marketing study and a completed Phase 2 trial. The TxGNN prediction aligns with established clinical practice. However, CPA is not currently registered in South Africa, and its significant prothrombotic risks require careful patient selection and monitoring.
To proceed, the following is needed:
- SAHPRA registration pathway determination (new application or Section 21 access)
- Detailed mechanism of action review (currently a data gap)
- Full safety profile from international prescribing information (EMA SmPC recommended)
- Thrombophilia screening protocol prior to prescribing (Factor V Leiden, Protein C/S, antithrombin levels)
- VTE risk assessment tool implementation for patient selection
- Clear documentation that predictions for thrombotic conditions (ranks 4-6, 10) and migraine with aura (rank 2) are reverse signals/contraindications, not therapeutic opportunities
This report is for research purposes only and does not constitute medical advice. Drug repurposing candidates require clinical validation before 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.