Table 2.
Clinical trials on the safety and efficacy of norethisterone acetate in comparison with other methods of treatment.
| Reference | Study design | Location | Population | Age group | Intervention | Comparator | Efficacy | Adverse events |
|---|---|---|---|---|---|---|---|---|
| Dean et al. (2019)65 | Case–control study and a pilot randomized controlled study | USA | 4 women who presented late in their cycle and desired avoiding vaginal bleeding within 10 days before wedding | 18–26 years | 5 mg NET | Age-matched controls that received OC pills | NET, begun on or before cycle day 12, is superior for women who desire to avoid breakthrough bleeding and maintain fertility when compared to OC pills; patient satisfaction was significantly higher in the NET group, with 80% willing to choose this method again | Spotting, weight gain, bloating, nausea, headache |
| Alaqzam et al. (2018)77 | Retrospective chart review to identify the most effective option for management of HMB in adolescents | USA | 73 adolescents with HMB | <21 years | 52 mg LNG-IUS (Mirena) | 5–10 mg/day NETA, combined OC, transdermal contraceptive patch, DMPA and tranexamic acid | LNG-IUS group (89%) had the highest rate of menstrual suppression followed by the NETA (83%) and transdermal patch (80%) groups | No adverse side-effects were observed |
| Kader et al. (2023)78 | Prospective observational study | India | 71 patients with AUB | 18–35 years | Group 1: NET (5 mg × 25 days) | Group 2: MPA (10 mg × 21 days) | NET was more effective than MPA | The drugs had no serious adverse effects |
| Vercellini et al. (2005)74 | Open-label, parallel-group, randomized, controlled trial | Italy | 90 women experiencing recurrent moderate or severe pelvic pain following conservative surgery for rectovaginal endometriosis | 18–35 years | 0.01 mg oral ethinyl oestradiol plus 3 mg/day cyproterone acetate | 2.5 mg/day NETA | Proportion of satisfied women was moderately, though not significantly, higher in the NETA group (73%) than in the intervention group (62%) | Weight gain, headache, nausea, depression, decreased libido, acne, bloating or swelling, breast tenderness, hypertriglyceridaemia, erythematous cutaneous reaction |
| Vercellini et al. (2012)90 | Patient preference, parallel cohort study | Italy | 154 women with persistent/recurrent severe deep dyspareunia after first-line surgery | Surgery: 35.0±4.7 years NETA: 34.3±5.0 years |
Conservative surgery at laparoscopy | Low dose of NETA (2.5 mg/day) | 43% women in the surgery group and 59% in the progestin group were satisfied (p=0.015) Surgery group: marked and rapid short-term dyspareunia score reduction, followed by partial recurrence of pain NETA group: pain relief effect was more gradual but progressive throughout the study period |
Weight gain, breakthrough bleeding, decreased libido, vaginal dryness, spotting, breast tenderness, bloating/swelling, headache, depression, nausea |
| Ferrero et al. (2014)81 | Prospective, non-randomized, open-label trial | Italy | 40 women with unilateral single endometrioma | 34.2±3.6 years | Oral NETA (2.5 mg/day) or a combination of oral letrozole (2.5 mg/day) | NETA (2.5 mg/day) | Volume of the endometriomas significantly decreased compared to baseline in both groups; it was smaller in the intervention group (p=0.026) | Breakthrough bleeding, depression, weight gain, insomnia, decreased libido, vaginal dryness, hot flashes, weight gain |
| Scala et al. (2018)82 | Patient preference prospective study | Italy | Women with endometriosis | 32.5±5.3 years | Group A: continuous oral treatment with 2.5 mg/day NETA | Group B: 91-day extended-cycle oral contraception (LNG/EE 150/30 μg for 84 days and EE 10 μg for 7 days) | No statistically significant difference in the rate of satisfied patients at 12 months between Group A (82.2%) and Group B (68.4%) (p=0.143) | Unscheduled bleeding/spotting |
| Lee et al. (2016)83 | Not mentioned | South Korea | 64 women who underwent laparoscopic surgery for endometriosis | GnRHa: 30.6±6.1 years Dienogest: 29.0±5.9 years |
GnRH agonist plus 17β-E2 and NETA (1.0 mg/day of 17β-E2 and 0.5 mg/day of NETA) | Dienogest (2 mg/day) | Visual analogue scale pain scores decreased significantly in both group with no significant inter-group differences | Menstruation-like bleeding and spotting, hot flashes, genital dryness, depression, sleep disorder, acne, headache, weight gain, decreased libido |
| Genazzani et al. (2013)84 | Double-blind, randomized, controlled study | 48 centres in Austria, Argentina, Denmark, Italy, Mexico, Russia and the USA | 662 postmenopausal women with spontaneous amenorrhea or spontaneous amenorrhea with serum follicle stimulating hormone levels 40 mIU/ml or had a bilateral oophorectomy without hysterectomy | 40–65 years | 0.25 mg drospirenone/0.5 mg 17β-E2 combination | 0.5 mg NETA/1.0 mg 17β-E2 | None of the participants groups had an endometrial biopsy result of ‘hyperplasia or worse’ | Breast pain, postmenopausal haemorrhage, cervical dysplasia, headache, endometrial hypertrophy, uterine leiomyoma, hot flash, weight gain, nausea, vulvovaginal mycotic infection, abdominal pain |
| Malik et al. (2020)85 | Comparative study on treatment of idiopathic HMB | Pakistan | 76 patients with regular bleeding and HMB and decreased haemoglobin levels | 35–45 years | Group A: LNG-IUS (Mirena) inserted into the uterus | Group B: 5 mg NET tablet prescribed thrice daily | Mean number of treatment days: Group A: 2.00±0.81 Group B: 3.63±0.75 LNG-IUS was more effective and associated with higher satisfaction rate |
No adverse side-effects |
| Rezk et al. (2016)86 | Randomized clinical trial | Egypt | 150 perimenopausal women with endometrial hyperplasia without atypia | >40 years | Group 1: LNG-IUS | Group 2: 15 mg MPA Group 3: 15 mg NETA |
Resolution of endometrial hyperplasia did not differ significantly between the three groups (p<0.05); LNG-IUS had the highest cost and acceptability (p<0.001) | Group 1: vaginal discharge Group 2: acne Group 3: nausea |
| Patel et al. (2012)87 | Randomized clinical study | India | 60 young girls | Age of menarche to 19 years with HMB | 5 mg NETA | Combined OC | Total mean improvement in the Menorrhagia Impact Questionnaire scores was higher in the NETA group than in the Combined OC group after three treatment cycles (21 versus 17); treatment failure was less in the NETA group than in the combined OC group | Breast tenderness, withdrawal bleeding, nausea, vomiting and water retention |
17β-E2, 17β-oestradiol; AUB, abnormal uterine bleeding; DMPA, depo-medroxyprogesterone acetate; GnRHa, gonadotropin-releasing hormone agonist; HMB, heavy menstrual bleeding; LNG-EE, extended-cycle oral contraception; LNG-IUS, levonorgestrel-releasing intrauterine system; MPA, medroxyprogesterone acetate; NET, norethisterone; NETA, norethisterone acetate; OC oral contraceptive.