Effect of norethisterone dose and duration in the management of abnormal uterine bleeding: a narrative review and case report.

Abnormal uterine bleeding (AUB) refers to a wide array of menstrual irregularities involving the frequency, duration and volume of flow. It is a common debilitating condition that is typically life-altering and rarely life-threatening. The prevalence of AUB varies with age and geographical region. AUB reportedly affects one-third of reproductive-aged women, with a higher incidence at menarche, perimenopause and postmenopause. 1 – 3 The most common symptom of AUB is heavy menstrual bleeding (HMB). 4 Women with AUB also experience severe pain, mood fluctuations, anxiety, abdominal bloating, diarrhoea, breast tenderness and increased urinary frequency. These symptoms create feelings of self-consciousness, embarrassment, fear of leaking or staining and worry regarding going out. 5 In adolescence, AUB is associated with pain, fatigue, limited physical and social activity, school absenteeism, concerns regarding breakthrough spotting and increased healthcare costs. 6 – 8 Thus, AUB significantly impacts women’s daily lives, including their family, job and lifestyle, and creates an economic burden. 5 Although these effects are an important motivation to seek medical care, several women first self-treat and wait to see if their condition improves. 5 In developing countries, where menstruation is often considered highly personal and secretive, fewer women seek medical attention for AUB. 9 However, the management of AUB requires thorough medical evaluation and individualized treatment. The present narrative review therefore aims to summarize the epidemiology and diagnosis of AUB, with a focus on the safety, efficacy and tolerability of the available first-line interventions for effective AUB management ( Figure 1 ).

A 40-year-old woman presented to the Apollo International Hospital, Guwahati, with an acute episode of HMB. Prior to this severe episode, her periods were normal with flow lasting 4–5 days and an average of 3–4 pads used per day. She had a medical history of sub-fertility and had undergone laparoscopic salpingectomy for a disturbed ectopic pregnancy, 2 years ago. She had a normal appetite, weight and sleeping patterns. She reported no substantial changes in bowel and bladder habits or recent initiation of a new medication. Her father had diabetes mellitus and hypertension. The patient was alert and co-operative but lethargic. Her blood pressure level was normal with a pulse rate of 104 bpm. She had an afebrile respiratory rate of 16 breaths per minute. She was pale without koilonychia, and no cyanosis, jaundice or mouth ulcers were observed. Dependent oedema was absent. Gynaecological examination revealed a bulky irregular mobile uterus without adnexal pathology. Basic laboratory tests demonstrated a haemoglobin level of 8.9 gm%, euglycaemia, euthyroidism and a normal coagulation profile and liver function. The peripheral smear and complete blood count tests revealed moderate iron deficiency. Transvaginal ultrasound examination revealed an irregular, enlarged uterus with an endometrial thickness of 8–9 mm without obvious pathology. Urine hCG findings were negative for pregnancy. Endometrial biopsy was planned to obtain an accurate diagnosis but the patient denied undergoing an invasive procedure. Following extensive counselling, the patient received 10 mg/day controlled-release NETA tablets (GYNASET CR 10, Mankind Pharma) from day 5 of the cycle/flow for 20 days. Follow-up revealed the satisfactory response of the patient to this treatment; therefore, 10 mg/day controlled-release NETA was continued cyclically from day 16 to day 25 for the next three cycles. Re-evaluation at the subsequent follow-up visit indicated that the patient was highly satisfied with the treatment and its outcomes. The prevalence of AUB has been studied in a few regions of India. Therefore, future survey studies are required to determine AUB prevalence in different parts of India, and elucidate the impact of geographical location and dietary patterns on the incidence of AUB in the Indian sub-continent. Further, the underlying cause of AUB can sometimes present a diagnostic challenge. Whilst aetiologies such as hormonal imbalance, uterine fibroids or polyps are commonly identified, the cause may remain unclear in some cases despite extensive evaluation. Advanced tools, such as non-invasive imaging and use of molecular biomarkers, could enhance diagnostic accuracy. In a recent review, Chodankar et al. 95 highlighted potential biomarkers of AUB, including metalloproteinases, epithelial-to-mesenchymal transition and chromosomal rearrangements on HMG2A , amongst several others. However, studies on biomarkers have been performed on a small number of samples, and further validation is necessary. Deep phenotyping of women with AUB may help to provide individualized care. 95 AUB often requires long-term management. Whilst short-term interventions, such as hormonal therapies or surgical procedures, may provide temporary relief, there is a need for a sustainable, long-term management strategy that can minimize recurrence and optimize a patient’s quality of life. Moreover, the side-effects of conventional treatment options often limit compliance and efficacy. AUB can significantly impact fertility, particularly when endometriosis or adenomyosis are present. 96 Preserving fertility whilst effectively managing AUB is a crucial consideration for many women of reproductive age. There is a clear unmet need for innovative and effective approaches that can ensure bleeding control, fertility preservation and patient compliance. 52 Most clinical studies have reported the efficacy and tolerability of NET (5 mg three times daily or 10 mg once daily for 3 weeks) in AUB management. 73 , 74 However, a shorter treatment duration may improve patient compliance and minimize adverse side-effects. Based on the severity of AUB, a thrice-daily 5 mg dose may be replaced by a single daily dose of 10 mg or 15 mg NET/NETA from day 5 to day 26 of the menstrual cycle to decrease the dosing frequency, and thereby improve patient compliance. Further, a daily dose of 10 mg/15 mg NET instead of a thrice-daily 5 mg dose for approximately 2 weeks could help effectively manage acute AUB. Therefore, future clinical trials are necessary to determine the efficacy of 15 mg NET taken once daily for 3 weeks in AUB management. Interventions for adolescents and young women with HMB and dysmenorrhea should be developed and implemented based on the needs of the patients to improve their quality of life. Education programmes for parents and teachers of adolescents with HMB and dysmenorrhea, health professionals (including general practitioners and specialists) and the general public, are likely to be useful in addressing these issues and managing expectations. 7 Therefore, future research should also focus on quantifying these needs in a large sample.

A PubMed search was conducted using keywords “abnormal uterine bleeding”, “norethisterone”, “uterine bleeding management”, “role of norethisterone in bleeding disorders” and “abnormal uterine bleeding and management”. In addition, MeSH terms “uterine bleeding”, “dysfunctional uterine bleeding”, “norethisterone” and “norethisterone acetate” were used during the search. This review included clinical trials (open trials, non-randomized controlled trials and randomized controlled trials), observational studies (retrospective and prospective, survey-based questionnaires, case reports and case series) and reviews (narrative reviews, clinical guidelines and meta-analyses) published between 2008 and 2023. The keywords and MeSH terms were also used to search a second database, Google Scholar, and results from the first five pages were screened for inclusion. In addition, we performed snowballing of relevant articles retrieved from both databases. Only articles published in English were included. The SANRA (Scale for the Assessment of Narrative Review Articles) criteria were followed for this narrative and non-systematic review. 10 Information retrieved through the above-mentioned searches was used to compile the present article.

AUB is indeed a significant health concern that profoundly impacts women’s lives, that of their families and society as a whole. Raising awareness regarding AUB, and ensuring that women have access to appropriate healthcare services is essential to mitigate its impact on individuals and society. Depending on the severity and cause of AUB, its management ranges from lifestyle modifications and hormonal therapies to more invasive procedures or surgery. Unfortunately, most hormonal therapies have side-effects that limit their efficacy. However, controlled-release formulations of NET/NETA could help maintain constant drug levels in the blood and exert minimal side-effects. Therefore, NET and NETA are promising therapeutic agents for effective AUB management.