Experience from the Clinics

Experience from the Clinics

What are the main treatment approaches for AUB?

Question and Answers The two main objectives of managing AUB are: 1) Controlling the current episode of heavy bleeding 2) Reducing menstrual blood loss in subsequent cycles In which age groups is abnormal uterine bleeding commonly reported? Treatment approach for AUB includes general measures, medical management, minimally invasive surgery and major Abnormal uterine bleeding is prevalent in women aged 30–49 years (at the extreme ages of a woman’s reproductive years) surgery. General measures include bed rest, tonics and vitamins to correct anaemia, treat hypertension or thyroid disease. with the overall prevalence of about 5%.1 However, abnormal bleeding can occur at any age. However, at certain times in a Hormonal management is considered the first line of medical therapy for patients with acute AUB without known or woman’s life, it is usual for periods to be somewhat irregular. Periods may not occur regularly when a girl first starts having suspected bleeding disorders. Treatment options include IV conjugated equine estrogen, combined oral contraceptives them (around age 9–14 years). During perimenopause (beginning in the mid–40s), the number of days between periods (OCs), and oral progestins. Antifibrinolytic drugs, such as tranexamic acid, work by preventing fibrin degradation and are may change. It also is normal to skip periods, or for bleeding to get lighter or heavier during perimenopause. effective treatments for patients with chronic AUB. Effective medical therapies include the levonorgestrel intrauterine system, OCs (monthly or extended cycles), progestin therapy (oral or intramuscular), tranexamic acid, and nonsteroidal Is obesity a risk factor for abnormal uterine bleeding? anti-inflammatory drugs. Patients with bleeding disorders or platelet function abnormalities should avoid nonsteroidal anti- inflammatory drugs. Obesity is a significant problem that is likely to increase the incidence of AUB in women. Obesity is also a risk factor for endometrial hyperplasia. In a large retrospective cohort study (n=916), it was found that half of the women were obese and The need for surgical treatment is based on the clinical stability of the patient, the severity of bleeding, contraindications endometrial biopsy showed that 5% of the women had complex endometrial hyperplasia with atypia or cancer.2 Obesity is to medical management, the patient’s lack of response to medical management, and the underlying medical condition of a predisposing underlying factor responsible for dysfunctional uterine bleeding (DUB). The onset of the abnormal uterine the patient. Surgical options include dilation and curettage (D&C), endometrial ablation, uterine artery embolization, and bleeding is significantly associated with weight changes1. Although guidelines suggest that age 45, or age 40 with obesity, hysterectomy.4 should be used as an indication for endometrial sampling in women with AUB, results from this study suggest that obesity (BMI ≥30 kg/m2) should be considered a more important risk factor than age.2 What are the differential diagnosis for AUB?

How does the International Federation of Gynecology and Obstetrics (FIGO) classify abnormal bleeding? Any bleeding from the genitourinary tract or gastrointestinal tract (GI tract) can mimic abnormal uterine bleeding. Therefore, bleeding from other sources fits into the differential diagnosis and must be ruled out. The differential diagnosis for genital The FIGO classification includes nine categories of abnormal bleeding arranged according to the acronym PALM-COEIN: tract bleeding is based on anatomic location or system: vulva, vagina, cervix, fallopian tubes and ovaries, urinary tract, four have objective visual criteria detected by imaging, biopsy, or pathology i.e., PALM: polyps; adenomyosis; leiomyomata; gastrointestinal tract, pregnancy complications, uterus.5 and malignancy and hyperplasia, while the remaining five are not directly related to structural abnormalities i.e., COEIN: coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified.3 What is the treatment recommendation for oral progesterone? ACCEPTED MANUSCRIPT Women who have contraindications or who cannot tolerate estrogen can use progestin. In women with AUB caused by Issue 3 | 2019 ovulatory dysfunction, continuous and cyclical administration of a systemic progestin has been shown to be effective P Polyp Coagulopathy C in reducing heavy menstrual bleeding and providing excellent cycle control. Commonly used medications include Norethisterone acetate (15 mg daily), medroxyprogesterone acetate (2.5–10 mg daily), micronized progesterone (200–400 6 Experience mg daily), and megestrol acetate (40–320 mg daily). H A B Norethisterone is the most commonly used oral progestogen in the treatment of heavy menstrual bleeding (HMB). Norethisterone 15 mg once daily tablet is prescribed from day 5 to day 26 of the menstrual cycle. This regimen shows A Adenomyosis Ovulatory O from the reduction in blood loss by >80%. Norethisterone is more commonly prescribed as a short-term measure, for example, to

7 the use of a Registered Medical Practitioner or Hospital LaboratoryFor only. terminate a heavy bleed or regulate menstruation for a holiday or an important life event. Long term clinical studies of sleev 8 Clinics Norethisterone have also demonstrated response rate of 73% after 6 months of treatment. CD I References L Leiomyoma Endometrial E 1. Nouri M, Tavakkolian A, Mousavi SR. Association of dysfunctional uterine bleeding with high body mass index and obesity as a main predisposing factor. Diabetes & Metabolic Syndrome: Clinical A: USS view of polyp Research & Reviews. 2014 Jan 1;8(1):1-2. B: Hysteroscopic view of polyp 2. Sharp H, Adelman M. ABNORMAL UTERINE BLEEDING. OBG Management. 2017 April, 29(4) 3. Whitaker L, Critchley HO. Abnormal uterine bleeding. Best Practice & Research Clinical Obstetrics & Gynaecology. 2016 Jul 1; 34:54-65. C: MRI of adenomyosis 4. Management of Acute Abnormal uterine bleeding. Obg management Reproductive-Aged Women. Available at: https://www.acog.org/Clinical-Guidance-and-Publications/Committee- E J : D: USS of adenomyosis Opinions/Committee-on-Gynecologic-Practice/Management-of-Acute-Abnormal-Uterine-Bleeding-in-Nonpregnant-Reproductive-Aged-Women?IsMobileSet=false. Accessed on: 28 May’ 19 E: Hysterectomy specimen containing fibroids 5. Davis E, Sparzak PB. Abnormal Uterine Bleeding (Dysfunctional Uterine Bleeding) [Updated 2019 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532913/ Malignancy Iatrogenic M F: Hysterectomy specimen containing I 6. Billow MR, El-Nashar SA. Management of abnormal uterine bleeding with emphasis on alternatives to hysterectomy. Obstetrics and Gynecology Clinics. 2016 Sep 1;43(3):415-30. 7. Maybin JA, Case Submitted by: sleev endometrial cancer Critchley HO. Medical management of heavy menstrual bleeding. Women’s Health. 2016 Jan;12(1):27-34. Developed by G: Histology of endometrioid carcinoma 7. Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Women’s Health. 2016 Jan;12(1):27-34. 8. Ashraf MN, Habib-Ur-Rehman A, Shehzad Z, et al. Clinical efficacy of levonorgestrel and norethisterone for the treatment of chronic abnormal uterine bleeding. J Pak Med Assoc. 2017;67(9):1331-1338 Dr. Jayanta Kumar Gupta H: Excessive bruising FG K I: USS of polycystic ovary M.B.B.S, MD (Gynaecology), DGO, MRCOG, FRCOG Apollo Clinic, Salt lake, J: Progesterone receptor localisation in Not otherwise N secretory phase classified Office Tower, City Centre K: levonorgestrel-releasing intrauterine system Salt Lake, Kolkata: 700064. (LNG-IUS) Disclaimer: The scientific content of this publication has been developed by Scientimed Solutions Pvt. Ltd. through an educational grant L: Doppler USS of AV malformation from Alembic Ltd. This publication is distributed free of cost as a service to the medical profession for educational purpose only. The expert comments expressed in this document are solely the views of the doctor. Alembic Ltd., does not agree nor disagree with the views expressed M: Doppler USS of endometrial pseudo-aneurysm L M in this document. Although, greatest possible care has been taken in compiling and checking the content of this booklet to be accurate and complete, the author, the developer or the sponsor shall not be responsible or in anyway liable for any injury and/or damage to any persons in view of any errors, omissions or inaccuracies in this publication, whether arising from negligence or otherwise. We request you to please refer to the full prescribing information for detailed information.

5 6 1 Experience from the Clinics Experience from the Clinics

Diagnosis Role of Norethisterone in treatment The patient was diagnosed with acute abnormal uterine bleeding with no structural abnormalities. Role of Norethisterone in postponing of abnormal uterine bleeding Treatment initiation Treatment continuation Other measures menstrual periods 15 mg Norethisterone once daily for 10 mg Norethisterone once daily till Folic acid 400 mcg supplementation first 5 days 25th day of the cycle was provided Introduction Introduction Menstruation can interfere with prescheduled holidays, upcoming important events or activities such as sports and Irregular menstrual cycle is one of the most common complaints among women reporting to Gynaecology departments. Consumption of iron-rich food was camping. Hence, some women choose to postpone or adjust their menstrual periods for varied practical reasons.1,2 A woman with abnormal uterine bleeding (AUB) experiences irregular menstrual cycle with respect to duration and recommended Amenorrhoea is effectively induced by continuous administration of a progesterone analogue.3 Available options frequency of bleeding, irregularity of menses, and blood volume loss. Treatment options available for AUB are usually for delaying menstruation, such as oral contraceptive pills, depot-medroxyprogesterone acetate injections as well as associated with treatment failure and/or hormonal side effects, thus leading to inefficacy, prevention of fertility and Follow-up after 1 month hormone releasing intrauterine devices are known to cause breakthrough bleeding or unpredictable spotting, resulting treatment non-compliance.1 Norethisterone is a widely used progesterone for treatment of abnormal uterine bleeding, in significant incidence of failure.3 Norethisterone presents as an effective and preferred alternative option for and is associated with significant improvement in menstrual blood loss and patient satisfaction.2,3,4 Improvement in menstrual blood loss Minimal side effects delaying menses, without causing any breakthrough (unscheduled) bleeding.3

The patient reported almost 80% improvement in blood Mild headache was experienced by the patient during the loss, with the treatment treatment Case presentation Case presentation Follow-up treatment recommendations Treatment regimen for next cycle Regularization of menstrual cycle A 28-year-old woman visited the Gynaecology clinic for advice about delaying her menstrual periods, since her wedding A 30-year-old woman reported to the Gynaecology 15 mg Norethisterone OD for initial 5 days Treatment was to be continued for another 2 months schedule was overlapping with the next menstrual cycle. department of the hospital, with complaint of excessive 10 mg OD up to 25th day Significant pain reduction and normal menstrual blood menstrual blood loss since 8 days, accompanied with pain. flow was attained Dosing of Norethisterone for postponement of menstrual periods ÂÂ Generally, dosing for postponement of menstruation is 5 mg tablet to be taken 3 times daily or 15 mg once daily before Discussion the expected onset of menstruation. Menstruation usually follows within 3 days of finishing the treatment Past Medical History Excessive menstrual blood loss has significant impact on physical, emotional, and overall quality of life in women with ÂÂ The patient reported no history of excessive menstrual bleeding or irregular menstrual cycles in the past abnormal uterine bleeding.1 Pharmacotherapy using hormonal and non-hormonal agents is the first choice in the Advantages of using Norethisterone for postponement of menstrual periods 4 ÂÂ She mentioned that she started experiencing irregularity of menstrual periods since past two months management of AUB. ÂÂ Norethisterone is commonly used as an effective and well-tolerated short-term measure to regulate or adjust menstrual periods for upcoming important events in life1,3,4 ÂÂ She was diagnosed with anaemia two years back Norethisterone in the management of abnormal uterine bleeding ÂÂ It delays menses effectively without causing spotting. Clinical evidence suggests that Norethisterone causes bleeding ÂÂ Since the past four months, the patient had been on rigorous vitamin and amino acid supplementation, as she had Norethisterone, a progestin, is the most frequently prescribed drug for abnormal uterine bleeding, given its cost- 3 3,4 withdrawal within 24-72 hours been diagnosed with muscle wasting and weakness effectiveness and absence of side effects. Norethisterone demonstrates suppression of endometrial development along with re-establishing predictable bleeding patterns, decreasing menstrual flow and lowering the risk of iron deficiency ÂÂ It has also demonstrated greater patient satisfaction rate of 80% compared to OCPs (p=0.041)3 ÂÂ No presence of other comorbid conditions was mentioned anaemia3 (Figure 1). ÂÂ Moreover, Norethisterone (daily dose of 15-30 mg) exhibits effective delay in menses as long as 7 months (inducing pseudopregnancy), even when administered as late as seven days after ovulation2 Clinical investigations Norethisterone in abnormal uterine bleeding ÂÂ In comparison to other hormonal formulations, another advantage of Norethisterone when used for long-term contraception is rapid return to fertility after discontinuation, since it weakly suppresses the hypothalamic-pituitary- 2  Weight: 47 kg, BMI: 19.8 kg/m Decreases menstrual blood Regularizes bleeding Suppresses endometrial Lowers the risk of iron- ovarian axis3 General examination  Body temperature: 37.7°C flow3 pattern3 development3 deficiency anemia3  Pallor: Positive Norethisterone is effective, well tolerated, and preferred option among women desiring a delay in their  Normal and healthy cervix Clinical studies of Norethisterone have demonstrated improvement in menstrual loss, indicated by reduction in the baseline menstrual periods.1,3,4 Pelvic examination  Normal uterus mean Pictorial Blood Assessment Chart (PBAC) score of 274 to 188 after 3 months of treatment with Norethisterone.3  Negative pap smear test Also, patient compliance and satisfaction play an important role in determining success of the treatment. Norethisterone ÂÂ It is an ideal and superior option compared to oral contraceptive pills since it prevents any breakthrough 3 Laboratory findings treatment has reported patient satisfaction rate of 70% in women with heavy menstrual bleeding.4 bleeding and maintains fertility Complete blood count (CBC) Normal References References Haemoglobin 9 g/dL - Anaemic 1. Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Womens Health (Lond). 2016;12(1):27-34. 1. Shakespeare J, Neve E, Hodder K. Is norethisterone a lifestyle drug? Results of database analysis. BMJ. 2000;320(7230):291. Thyroid stimulating hormone 0.8 mIU/L - Normal 2. Dhananjayan D, Mirunalin. Comparative study between ormeloxifene and norethisterone in the improvement of menstrual blood loss (MBL) 2. Greenblatt RB, Jungck EC. Delay of menstruation with Norethisterone, an orally given progestational compound. J Am Med Assoc. in abnormal uterine bleeding. International Journal of Current Medical And Pharmaceutical Research. 2016;2(10):758-761. 1958;166(12):1461-3. Pelvic ultrasound 3. Gett S, Singh S. The efficacy and safety of norethisterone in the management of menorrhagia of dysfunctional uterine bleeding.Indian Journal 3. Dean J, Kramer Katherine, Akbary F, et al. 2019. Norethisterone is superior to combined oral contraceptive pills in short-term delay of menses  Normal uterus and cervix of Maternal-Fetal & Neonatal Medicine. 2018;5(1):63-67. and onset of breakthrough bleeding: a randomized trial. BMC Women’s Health. 19. 10.1186/s12905-019-0766-6. Trans-abdominal imaging  Normal endometrium size and structure 4. Kiseli M, Kayikcioglu F, Evliyaoglu O, et al. Comparison of therapeutic efficacies of norethisterone, tranexamic acid and levonorgestrel-releasing 4. Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Womens Health (Lond). 2016;12(1):27-34.  Absence of adnexal mass intrauterine system for the treatment of heavy menstrual bleeding: A randomized controlled study. Gynecol Obstet Invest. 2016;81(5):447-53.

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