Table 1.

Clinical trials on the safety and efficacy of norethisterone acetate alone or in comparison with placebo.

Reference	Study design	Location	Population	Age group	Intervention	Comparator	Efficacy	Adverse events
Boruah et al. (2021)61	Retrospective analysis of women with ovulatory AUB	40 centres in India	308 women with ovulatory AUB	18–45 years	10 mg/day CR-NET for 10 days	None	Most women (63%) experienced styptic action of 10 mg CR-NET within 4 hours of administration 61% did not report any incidence of breakthrough bleeding 70% reported withdrawal bleeding within 24–72 hours of taking the last dose	No adverse events
Bonassi Machado et al. (2023)67	Multicentre, double-blind, placebo-controlled, randomized clinical trial	Brazil	118 postmenopausal women with moderate to severe vasomotor symptoms	45–60 years	Combination of 17β-E2 and NETA: 0.5 mg 17β-E2/0.1 mg NETA	Placebo	The frequency of vasomotor symptoms reduced by 77.1% in the treatment group versus 49.9% in the placebo group (p=0.0001)	Headache, breast tenderness, increased vaginal bleeding, hypercholesterolaemia
Ferrero et al. (2010)68	Prospective pilot study	Italy	40 women with colorectal endometriosis, who had pain and gastrointestinal symptoms	33.7±4.4 years	2.5 mg/day NETA In case of breakthrough bleeding after 2 months of treatment, the NETA dose was increased by 2.5 mg/day (maximum dose of 5 mg/day)	None	NETA intake significantly improved the intensity of chronic pelvic pain, deep dyspareunia and dyschezia	Uterine bleeding/spotting (scanty bleeding not requiring usual sanitary protection); breakthrough bleeding (light or moderate bleeding requiring sanitary protection); and metrorrhagia (more than normal menstruation)
Morotti et al. (2017)69	Retrospective cohort study	Italy	103 women with pain symptoms caused by rectovaginal endometriosis	30.5±3.5 years	2.5 mg/day, up to 5 mg/day, NETA	None	68.8% of the 61 women completing the study were satisfied or very satisfied with long-term NETA treatment	Weight gain, breakthrough bleeding, migraine attacks, decreased libido, lipid alteration, depression
Taniguchi et al. (2017)70	Preliminary study	Japan	6 women with unilateral ovarian endometriomas	39–48 years	5 mg/day NET	None	The size of ovarian endometrioma decreased after treatment; all patients were relieved from dysmenorrhea	No serious adverse effects of NET use
Santos et al. (2014)71	Retrospective cohort study to assess the effectiveness of NET taper in the management of acute heavy menstrual bleeding in adolescents	USA	176 adolescent females	14.8±2.3 years	0.35 mg NET	None	20 patients required NET taper for heavy bleeding; of this group, 78.9% experienced complete cessation of bleeding within 7 days	Irregular bleeding and systemic side-effects (nausea/vomiting, mood swings, hot flashes) were associated with discontinuation; no serious adverse events (venous thromboembolism, cardiovascular events) were reported
Muneyyirci-Delale et al. (2012)72	Retrospective chart review to study the effectiveness of NETA in the management of adenomyosis	USA	28 premenopausal women with moderate to severe pelvic pain and bleeding	27–49 years	5 mg NETA daily at beginning of menstrual cycle as “3 weeks on” and “1 week off” regimen	None	Pain and bleeding decreased from pretreatment levels (p<0.001); dysmenorrhea scores before and after treatment were 62.5±9.1 versus 11.3±3.1, respectively (p<0.001); bleeding scores before and after treatment were 28.1±2.4 and 8.1±8.5, respectively (p<0.001); none of the patients reported breakthrough bleeding after 2 months	Fewer and milder side-effects
Papapanagiotou et al. (2019)73	Prospective audit focused on the effect of high NET doses in adolescents with AUB	Greece	29 females	11–17 years	Girls <55 kg were administered 5 mg NET two to three times a day, whereas for heavier adolescents, the starting dose was higher at 5–10 mg three times a day	None	Vaginal bleeding stopped at a mean of 46.1 (range, 8–120) hours after initiating NET	No serious adverse events
Taneja et al. (2019)74	Prospective observational study on women with AUB post-abortion	India	30 women with AUB post-abortion	31–34 years	10 mg oral NET twice daily × 3 weeks, for a maximum of three cycles	None	Most patients had complete resolution of symptoms after a single 3-week course, whilst some remained symptomatic and required a second course	NET was well tolerated, and none of the patients suffered any major adverse effects
Boruah et al. (2021)61	Retrospective analysis of women with ovulatory AUB	40 centres in India	308 women with ovulatory AUB	18–45 years	10 mg/day CR-NET for 10 days	None	Most women (63%) experienced styptic action of 10 mg CR-NET within 4 hours of administration; 61% did not report any incidence of breakthrough bleeding; 70% reported withdrawal bleeding within 24–72 hours of taking the last dose	No adverse events
Ayalon et al. (2022)75	Prospective questionnaire-based study to examine the effectiveness of NETA on vaginal bleeding caused by POP	Israel	120 women experiencing vaginal bleeding due to POP	20–44 years	5 mg/day NETA after a 5-day pause after taking POP	None	Women who added 5 mg NETA to POP contraception reported a significant reduction in the frequency of bleeding after 2, 4 and 6 weeks of treatment	No adverse effects

17β-E2, 17β-oestradiol; AUB, abnormal uterine bleeding; CR, controlled release; NET, norethisterone; NETA, norethisterone acetate; POP, progesterone-only pills.