Progesterone
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Progesterone: From Endometriosis to Amenorrhea
One-Sentence Summary
Progesterone is a natural steroid hormone, originally used for endometriosis, endometrial conditions, and menopause-related conditions such as osteoporosis and atrophic vaginitis. The TxGNN model predicts it may be effective for amenorrhea, with 4 clinical trials and 19 publications compiled for this direction. However, the trials mostly test estrogen-based hormone replacement, so direct evidence for progesterone alone is limited.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Endometriosis (the Singapore licence records contain no approved indication text; this is taken from the knowledge-graph indication list) |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.99% |
| Evidence Level | L2 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, progesterone is a natural female sex hormone that works together with estrogen to control the cyclic growth and shedding of the endometrium. It is already used for endometrial and menopause-related conditions, and mechanistically may be applicable to amenorrhea.
In estrogen-primed women, stopping progesterone triggers endometrial shedding. This is the basis of the "progestin challenge" used in diagnosing secondary amenorrhea, and of its therapeutic use. A 2024 review of oral micronized progesterone in endocrinology (PMID 38652231) also discusses its diagnostic and therapeutic roles.
An important caveat: the listed trials mostly test estrogen (with cyclic progesterone in some) in women with hypoestrogenic amenorrhea (athletes, anorexia nervosa, premature ovarian insufficiency). Their outcomes are bone density, cardiovascular and cognitive effects, not progesterone alone for amenorrhea itself.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00946192 | Phase 3 | Completed | 121 | Transdermal or oral estrogen vs no estrogen for bone density in young athletes with amenorrhea (estrogen-based) |
| NCT00088153 | Phase 2/3 | Completed | 110 | Estrogen replacement for bone mass in adolescents with anorexia nervosa |
| NCT03740204 | Phase 2 | Active, not recruiting | 120 | Transdermal estradiol with cyclic progesterone vs placebo on cognition and reward in hypoestrogenemic eating disorders |
| NCT03018366 | Phase 2 | Completed | 29 | Cardiovascular risk factors and inflammation in young women with functional hypothalamic amenorrhea |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38652231 | 2024 | Review | Rev Endocr Metab Disord | Diagnostic and therapeutic use of oral micronized progesterone in endocrinology |
| 33716979 | 2021 | Review | Front Endocrinol | Causes and treatment options in premature ovarian insufficiency |
| 8629565 | 1996 | Review | Am Fam Physician | Diagnostic evaluation of amenorrhea |
| 32233689 | 2020 | Review | Climacteric | Clinical management of postmenopausal vaginal bleeding |
| 20414 | 1977 | Cohort | Int J Fertil | 356 patients with secondary amenorrhea: causes and recovery rates over 6 years |
| 34405378 | 2022 | Review | Rev Endocr Metab Disord | Hormonal treatments for endometriosis and their endocrine background |
| 28257537 | 2017 | Review | South Med J | Primary ovarian insufficiency; hormone replacement for secondary amenorrhea |
| 22283375 | 2012 | Review | Gynecol Endocrinol | Neuroendocrine control of ovulation and causes of amenorrhea |
| 7457308 | 1980 | Review | Am Fam Physician | Amenorrhea work-up, including withdrawal bleeding after progesterone |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN03626P | CYCLOGEST PESSARY 400 mg | Suppository | Not stated in the records |
| SIN10884P | CRINONE PROGESTERONE VAGINAL GEL 8% | Gel | Not stated in the records |
Safety Considerations
- Contraindications (from the knowledge graph, not label text): hypertension, liver failure and liver disease, epilepsy, porphyria, kidney disease, gallbladder disease, hyperglycaemia and diabetes mellitus (including diabetic ketoacidosis), hypothyroidism, osteoporosis, systemic lupus erythematosus, asthma, anxiety and neurotic disorders, hypertriglyceridaemia, and substance abuse/dependence.
- Drug Interactions: 100 interactions were found, all of the examples shown are Moderate. They are mainly with antidiabetic drugs, including metformin, pioglitazone, acarbose, GLP-1 agonists (semaglutide, liraglutide, dulaglutide), SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin), DPP-4 inhibitors (alogliptin, saxagliptin), sulfonylureas and insulins. Other examples are aprepitant and clarithromycin.
Please also refer to the package insert for the full warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Progesterone has a well-established physiological role in the menstrual cycle, and progestin challenge is standard practice in amenorrhea work-up. However, the supporting trials test estrogen-based replacement and the literature is largely review-level, so evidence for progesterone alone is indirect.
To proceed, the following is needed:
- Package insert warnings and contraindications for the two Singapore-registered products (including their approved indications)
- Detailed mechanism of action data
- Trials or analyses testing progesterone specifically for amenorrhea
- A safety plan for patients with comorbidities (diabetes, hypertension, liver disease) and for antidiabetic drug interactions
- Confirmation that the registered routes (vaginal pessary and vaginal gel) suit the intended amenorrhea use, since this has not been assessed
Other predicted indications (for reference): The 9 lower-ranked predictions are weaker. Fibrocystic breast disease, benign mammary dysplasia, cervix endometriosis, rectovaginal septum endometriosis, scar endometriosis are research questions (L4) with no clinical trials. Bilateral renal hypoplasia, renal hypoplasia, apocrine adenosis and blunt duct adenosis of the breast have no credible supporting evidence (L5) and should be held.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.