Progesterone
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Progesterone: From Its Registered Use to Amenorrhea
One-Sentence Summary
Progesterone is a natural steroid hormone, marketed in South Africa as an oral capsule (Utrogestan). The SAHPRA data supplied do not state its approved indication. The TxGNN model predicts it may be effective for Amenorrhea, with a very high score. The search retrieved 50 registered trials and 18 publications, but none is a direct test of progesterone for treating amenorrhea, so the evidence is indirect (Level L4).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not stated in the SAHPRA licence data supplied |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.9996% |
| Evidence Level | L4 |
| South Africa Market Status | Marketed |
| Number of SAHPRA Registrations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the Evidence Pack. Progesterone is a natural steroid hormone. A 2024 review (PMID 38652231) describes how it helps control the pulsatile release of LH and FSH through kisspeptin, neurokinin B and dynorphin neurons in the hypothalamus. Together with oestradiol, it also drives the cyclic changes in the endometrium.
Amenorrhea most often arises from disruption of the hypothalamic-pituitary-ovarian axis. In oestrogen-primed patients, progesterone withdrawal induces endometrial shedding. A progestogen challenge is therefore a standard diagnostic and treatment step in amenorrhea work-ups. This is the main basis for the prediction.
An important caveat: progesterone may already carry a labelled use for secondary amenorrhea. The original indication field in the pack is empty. The SAHPRA-approved Professional Information (PI) must be checked before this is treated as true repurposing.
Clinical Trial Evidence
The search retrieved 50 trials. The table lists the 10 most relevant. None of them tests progesterone alone as the primary treatment for amenorrhea. Most describe the condition, or test other drugs in amenorrhea populations. No SANCTR or PACTR registrations were found.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03309176 | Phase 4 | Completed | 42 | Tests whether a progesterone-induced withdrawal bleed is needed before clomiphene ovulation induction in women with oligo/amenorrhea |
| NCT05312190 | N/A | Unknown | 330 | Compares Zhenqi Buxue oral liquid, progesterone capsules, or both in menstrual disorders |
| NCT03740204 | Phase 2 | Recruiting | 120 | Transdermal estradiol with cyclic progesterone vs placebo in hypoestrogenic young women with restrictive eating disorders |
| NCT06533865 | Phase 3 | Recruiting | 114 | Romosozumab added to oestrogen replacement for bone density in functional hypothalamic amenorrhea; gives condition context only |
| NCT00946192 | Phase 3 | Completed | 121 | Transdermal or oral oestrogen vs none for bone density in amenorrheic adolescent athletes |
| NCT01185782 | Phase 3 | Completed | 300 | SJ-0021 vs purified pituitary gonadotropin in amenorrhea I or anovulatory cycles; different drug, no progesterone data |
| NCT01674426 | N/A | Completed | 17 | Cognitive behaviour therapy vs observation in functional hypothalamic amenorrhea |
| NCT07224438 | Phase 2 | Recruiting | 20 | Subcutaneous kisspeptin to stimulate reproductive hormones and ovulation in hypothalamic amenorrhea |
| NCT02858336 | N/A | Completed | 38 | CaREFREE study of diet, exercise and other factors in functional hypothalamic amenorrhea |
| NCT03018366 | Phase 2 | Completed | 29 | Cardiovascular risk markers in young women with functional hypothalamic amenorrhea |
Literature Evidence
The retrieved publications are mainly reviews and background papers. The pack contains no randomised trial of progesterone in amenorrhea.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38652231 | 2024 | Review | Rev Endocr Metab Disord | Diagnostic and therapeutic use of oral micronized progesterone in endocrinology; describes its role in gonadotropin control and endometrial cycling |
| 35525789 | 2022 | Review | Curr Probl Pediatr Adolesc Health Care | Causes and management of amenorrhea in adolescents and young adults; most cases stem from hypothalamic-pituitary-ovarian axis dysfunction |
| 33716979 | 2021 | Review | Front Endocrinol | Causes, symptoms and treatment options in premature ovarian insufficiency |
| 28257537 | 2017 | Review | South Med J | Primary ovarian insufficiency; secondary amenorrhea commonly requires hormone replacement therapy |
| 22283375 | 2012 | Review | Gynecol Endocrinol | Neuroendocrine control of ovulation; hypothalamic failure leads to anovulation and amenorrhea |
| 8629565 | 1996 | Review | Am Fam Physician | Diagnostic evaluation of amenorrhea; pregnancy must be excluded first, then check prolactin and TSH |
| 945033 | 1976 | Case series | Ann Intern Med | 15 patients with galactorrhea-amenorrhea treated with bromocriptine; progesterone levels failed to show ovulatory peaks before treatment |
| 36653588 | 2023 | Review | Reprod Sci | Methods for repairing injured endometrium, a cause of amenorrhea |
| 18756412 | 2008 | Review | Semin Reprod Med | Intrauterine adhesions (Asherman’s syndrome), ranging from amenorrhea to normal menses |
| 35463307 | 2022 | Meta-analysis | Front Oncol | Chemotherapy-induced amenorrhea and its prognostic significance in premenopausal breast cancer |
South Africa Market Information
| Registration Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| A40/21.8.2/0771 | Utrogestan | Capsule (oral) | Not stated in the data supplied |
The only registered form is an oral capsule. Essential Medicines List (EML) status is not given in the Evidence Pack.
Safety Considerations
Please refer to the SAHPRA-approved Professional Information (PI) for safety information. Report adverse drug reactions to SAHPRA.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The prediction score is very high, but no retrieved study tests progesterone as a treatment for amenorrhea. The mechanistic link rests on reviews and indirect trials.
- Warnings and contraindications from the package insert are missing, which blocks safety screening. The current label may already cover secondary amenorrhea, so it is unclear whether this is genuine repurposing.
- The other nine predicted indications in the pack (for example benign breast conditions, endometriosis sites and renal hypoplasia) have model-only or receptor-profiling evidence and are also on Hold.
To proceed, the following is needed:
- Download the SAHPRA package insert for Utrogestan (Reg. No. A40/21.8.2/0771) to confirm the approved indication and to obtain warnings and contraindications
- Mechanism of action data from DrugBank
- Confirmation of whether amenorrhea is already a labelled use; if it is, the case is label alignment rather than repurposing
- Randomised or controlled evidence of progesterone in primary or secondary amenorrhea, or a targeted systematic review
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.