Norethisterone

Evidence Level: L4

Predicted Indications: 1

Norethisterone
Norethisterone: From Endometriosis and Menopausal Conditions to Amenorrhea

## Pharmacist Assessment Report

Norethisterone: From Endometriosis and Menopausal Conditions to Amenorrhea

One-Sentence Summary

Norethisterone is a synthetic progestin, originally used for conditions such as endometriosis, primary ovarian failure and postmenopausal osteoporosis (including in combination with estradiol as a transdermal patch). The TxGNN model predicts it may be effective for amenorrhea, but no clinical trials are registered and the 20 publications retrieved are mostly contraceptive reviews, so direct supporting evidence is weak.

Quick Overview

Item	Content
Original Indication	Endometriosis, primary ovarian failure, postmenopausal osteoporosis, postmenopausal atrophic vaginitis (the UK licence record contains no indication text)
Predicted New Indication	Amenorrhea
TxGNN Prediction Score	99.60%
Evidence Level	L4
UK Market Status	Marketed
Number of Marketing Authorisations	1
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in the data compiled for this report. Based on general pharmacology, norethisterone is a synthetic progestin that acts as a progesterone receptor agonist. Progestins are established in the management of secondary amenorrhea, where a progestin withdrawal challenge induces endometrial shedding if the endometrium has had oestrogen priming. They are also used for cycle regulation.

This fits with the original indications. Endometriosis and primary ovarian failure both involve hormone-responsive endometrial and ovarian tissue, so a mechanistic link to menstrual disorders is biologically plausible.

However, the retrieved literature does not address amenorrhea treatment directly. Most papers are contraceptive reviews in which amenorrhea appears as a side effect or bleeding-pattern outcome rather than a treatment target. The high TxGNN score is a computational prediction and does not substitute for clinical evidence.

Clinical Trial Evidence

Currently no related clinical trials registered.

Literature Evidence

Of the publications retrieved, the following are the most relevant. None tests norethisterone as a treatment for amenorrhea.

PMID	Year	Type	Journal	Key Findings
38530848	2024	RCT	PloS one	WHICH trial comparing DMPA-IM and norethisterone enanthate injectables on estradiol levels, menstrual effects, mood and sexual activity
8336583	1993	Randomised trial	The Medical Journal of Australia	Continuous low-dose oestrogen and progestogen HRT; efficacy and acceptability of three progestogens
41489365	2026	Cohort	Biology of Reproduction	Secondary analysis of 521 women: injectable contraceptives affect the hypothalamic-pituitary-ovarian axis, with more amenorrhea with DMPA-IM than norethisterone enanthate
23641480	2013	Systematic review	Cochrane Database of Systematic Reviews	Combination injectable contraceptives: effectiveness and bleeding-pattern changes
18843662	2008	Systematic review	Cochrane Database of Systematic Reviews	Earlier version of the review of combination injectable contraceptives
6786825	1981	Phase I trial	Contraception	20 Cuban women given norethisterone enanthate or norethisterone acetate; ovulatory LH/FSH peaks abolished, menstrual disorders including amenorrhea reported
3695501	1987	Review	Journal of Steroid Biochemistry	Norethisterone contraceptive microspheres; amenorrhea and spotting among the main side effects
6230212	1983	Survey	Contraception	Survey of approaches to managing menstrual disturbances with injectable progestogens
31056890	2019	Case report	JBRA Assisted Reproduction	Autoimmune hypothyroidism with intermittent ovarian failure in a woman with secondary amenorrhea and infertility
12290848	1994	Review	Journal of Obstetrics and Gynaecology	Review of once-a-month combined injectable contraceptives

UK Market Information

Marketing Authorisation Number	Product Name	Dosage Form	Approved Indication
0604011L0AAAXAX	Estradiol/Norethisterone Patch 50/170 mcg	Not specified	Not specified

This identifier does not follow the usual MHRA “PL XXXXX/XXXX” format, so the licence details should be verified against the MHRA register. NICE-appraised indications and BNF classification were not available in the data compiled for this report.

Safety Considerations

Contraindications (suggested by knowledge-graph associations, not label text): hypertension, epilepsy, porphyria, kidney disease, liver disease, gallbladder disease, diabetes mellitus and hyperglycaemia, hypertriglyceridaemia, hypothyroidism, systemic lupus erythematosus, asthma, hypercalcaemia, and female breast carcinoma. These must be verified against the SmPC.
Drug Interactions: 159 interactions were identified. All 20 listed are of moderate severity. They are mainly with glucose-lowering agents (acarbose, metformin, dapagliflozin, linagliptin, nateglinide, GLP-1 agonists and insulins), plus aprepitant, clotrimazole, metreleptin and prucalopride.

Please refer to the SmPC and BNF for full safety information. Report suspected adverse reactions via the Yellow Card Scheme.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN score is high and progestins have a plausible role in secondary amenorrhea. However, there are no registered trials, and the literature concerns contraception rather than treatment of amenorrhea, so the evidence level is only L4.

To proceed, the following is needed:

Mechanism of action data to support the mechanistic reasoning
Clinical studies or guideline evidence directly assessing norethisterone for amenorrhea
UK licence details (indication, dosage form and a verified PL number) and SmPC safety information
Assessment of route compatibility, since the UK authorisation is a transdermal oestrogen-progestin patch
Review of the knowledge-graph contraindications, particularly cardiometabolic and hepatic conditions, against the SmPC
Disclaimer

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