2,3Resident, Department Of obstetrics and Gynae, BPS Government Medical College for Women, Khanpur Kalan (Sonepat), Haryana, India- 131305
4Consultant Gynaecologist, AMH and IC, Gohana (Sonepat), Haryana, India- 131301
The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) has designed the PALM-COEIN classification system to define causes of AUB5. The components of PALM group include structural causes: Polyp (P), Adenomyosis (A), Leiomyoma (L), Malignancy (M) and COEIN group includes nonstructural causes: Coagulopathy (C), Ovulatory Disorders (O), Endometrial Disorders (E), Iatrogenic Causes (I), and Not Classified (N). The classification also defined intermenstrual bleeding (IMB) as it occurs between clearly defined cyclic and predictable menses while AUB was referred to as bleeding that is abnormal in volume, regularity and/or timing.
All patients presenting with HMB should have a full blood count taken to exclude significant anaemia, classified as hemoglobin of less than 10 g/dL. The platelet level should be assessed, as conditions such as ITP causing thrombocytopenia are a known, although rare, causes of HMB. For patients in whom heavy menstrual bleeding has been present since menarche and/or the family history is suggestive of a bleeding disorder, a coagulation profile should be performed. Investigations for specific bleeding disorders are indicated only if the coagulation profile is abnormal.
Ultrasound evaluation is indicated in the event of abnormal findings and is the imaging modality of first choice. Imaging of the pelvis should be performed if the uterus is palpable abdominally, if bimanual examination reveals a pelvic mass and/or if initial pharmacological management fails. The finding of intramural uterine fibroids less than 3 cm diameter does not constitute a significant ultrasound abnormality, unless multiple fibroids are present. The finding of sub mucosal fibroids on ultrasound indicates that Mirena insertion is not likely to be an effective management strategy, with a high risk of expulsion; however, other hormonal and non-hormonal treatments are appropriate.
An endometrial biopsy should be performed in all women aged 45 years or older with new-onset or worsening HMB to exclude endometrial carcinoma or hyperplasia. Endometrial biopsy should be performed in women under 45 years who have menorrhagia associated with obesity or PCOS (chronically increased estrogen exposure) in whom the risk of endometrial cancer is increased. Endometrial biopsy is also indicated in the context of failed medical management and in women at high risk of endometrial cancer (e.g family history, tamoxifen use, Lynch syndrome). Various endometrial sampling devices (Endosampler, Endocurette, Pipelle) are currently used in gynaecological practice.
Hysteroscopy is appropriate when there is regular unscheduled vaginal bleeding (intermenstrual or post-coital bleeding), when ultrasound suggests an endometrial polyp, or when endometrial carcinoma is suspected on ultrasound assessment. It is not a mandatory investigation in all women presenting with HMB, as the likelihood of endometrial pathology is very low in younger women. Patient age, symptom severity, associated symptoms and clinical risk factors should drive the intensity of investigation.
NSAIDs are a first-line medical therapy in ovulatory menorrhagia. Recent evidence reviewed by the National Institute for Health and Clinical Excellence showed that the use of NSAIDs in the management of menorrhagia was associated with a 20% to 40% significant reduction in blood loss. Mefenamic acid was associated with a 29% reduction in menstrual flow, whereas naproxen and ibuprofen were also associated with a 26% and 16% reduction, respectively, although they are not licensed for menorrhagia .
Tranexamic acid, a plasminogen activator inhibitor, controls menorrhagia by inhibiting the dissolution of thrombosis. Lethaby and colleagues  reported that the use of antifibrinolytic therapy was associated with a greater reduction in HMB when compared with placebo or other medical therapies such as NSAIDS, oral luteal phase progestogens, and ethemsylate. The review undertook a meta-analysis of two randomized clinical trials of Tranexamic acid versus placebo and found a difference of 93.96 mL (95% CI, 151.43 mL to 36.49 mL; P = 0.001), in favor of treatment .
Combined oral contraceptives (COCs) are believed to work by regulating the cycle and thinning the endometrium, which eventually leads to a lighter withdrawal bleed. The majority of COCs are monophasic; that is, they are dosed at the same strength throughout the 21-day treatment phase. COCs are generally used in 21-day treatment cycles followed by a 7-day break, during which time endometrial breakdown and loss occurs. Such withdrawal bleeding is physiologically different from the bleeding that occurs after a natural ovulatory cycle.
Progesterone is a physiologic hormone responsible for secretory transformation of the endometrium, and bleeding occurs when endogenous levels of estrogen and progesterone fall if fertilization does not occur. The mechanisms by which oral progestogens reduce MBL are not fully understood . The first review, published in 1995 and comprising four randomized clinical trials, showed that norethisterone had no effect on MBL (MBL percentage change: 95% confidence interval [CI], 6.1% to +1.1%) .
The LNG-IUS is an intrauterine, long-term progestogen-only method of contraception licensed for 5 years of use. The device consists of a T-shaped plastic frame with a rate-limiting membrane on the vertical stem containing 20 µg of levonorgestrel. The levonorgestrel is released in a controlled dose over 24 hours for up to 5 years. The effects of the LNG-IUS are mostly local and hormonal; it prevents endometrial proliferation and causes thickening of cervical mucus. Two recent systemic reviews demonstrated a 71% to 96% reduction in menstrual blood flow and amenorrhea in 20% to 30% of women when the LNG-IUS was used [18-19].
In the event that medical therapies prove to be ineffective, the patient should be transferred to secondary care for further management.
The choice between surgical options and medical therapies for the management of HMB is dependent on the age of the woman, the extent to which the HMB is affecting her life, and her contraceptive needs. In the majority of cases, surgical options are only really explored once medical therapies fail. A recent systematic review assessed the long-term benefits of medical versus surgical therapies and showed that, in secondary care facilities, surgical management of HMB has a slight advantage over medical treatment, which diminishes over time (control of bleeding at 5 years [n = 140] OR, 1.99 [95% CI, 0.84–4.73]) in favor of surgery.
In the 1990s, if medical therapies failed to control HMB, hysterectomy was the only definitive surgical option available. Since then, a number of surgical options have been developed. Endometrial ablation destroys and removes the endometrium along with the superficial myometrium. First-generation endometrial ablation involved distending the uterine cavity with fluid and resecting the tissue with an electrosurgical loop.
In women in whom fibroids are the cause of the HMB, two further surgical options are available: uterine artery embolization (UAE) and myomectomy. UAE is usually performed by an interventional radiologist on a sedated patient. It involves injecting small polyvinyl particles into the uterine arteries through a catheter that is inserted via the femoral artery; this causes the eventual blockage of the feeding capillaries associated with the myoma. The eventual loss of the blood supply to the fibroids causes them to shrink, thereby allowing us to treat the cause of the HMB.
Although the most radical form of management of HMB, hysterectomy does provide a definitive cure for menorrhagia. It involves the surgical removal of the uterus. Until approximately the 1990s, hysterectomy was considered as the only viable surgical treatment for HMB. Because of the morbidities associated with a hysterectomy, the permanent repercussions of the surgery, and its cost to the National Health Service, there is a strong incentive to reduce the number of hysterectomies performed and to encourage conservative modes of treatment such as the LNG-IUS, endometrial ablation, and UAE as management options for HMB. Since the development of new pharmaceutical and less invasive surgical options, the number of hysterectomies in the United Kingdom has decreased (from 24,355 in 1993 down to 10,559 in 2002) . Concurrently, advances in endoscopic technologies such as diathermy, laser, and ultrasonic energy have enabled most hysterectomies to be performed with minimally invasive techniques. More conservative, effective, and medical interventions are currently being developed and should provide additional alternatives to hysterectomy.
Gonadotropin-releasing Hormone Antagonists
Uterine fibroids are often the cause of HMB in women, and their growth is often dependent on ovarian steroids. Therefore, it was hypothesized that a pharmacologically induced hypoestrogenic state, similar to menopause, should decrease their growth and consequently the associated HMB. Gonadotropin-releasing hormone (GnRH) antagonists have been shown to be effective in creating this pseudomenopausal environment by competing with endogenous GnRH for binding sites in the pituitary gland, causing a reduction in gonadotropin release.
Among the selective estrogen receptor modulators (Clomifene, Tamoxifen, Toremifene, Raloxifene, Ospemifene and Bazedoxifen), Ormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), is currently undergoing clinical evaluation for the treatment of HMB. Its beneficial role in the treatment of menorrhagia was observed when it regulated dysfunctional uterine bleeding and improved endometriosis symptoms in women using it as a form of contraception .
Progesterone antagonists such as mifepristone are commonly used for the evacuation of the pregnant uterus and for the induction of labor. It has also been extensively used in research settings as a possible treatment for fibroids. A systematic review by Samuel and Clark  analyzed six studies that used mifepristone as a treatment option for women with HMB associated with uterine fibroids; uterine blood loss ranged from 27% to 49%.
Selective progesterone receptor modulators have been reported to induce an antiproliferative effect on the endometrium, although the exact mechanism of action is not clear. Trials assessing the effectiveness of asoprisnil in the management of HMB showed reduction in menstrual flow proportionate to the dose prescribed .
Aromatase inhibitors markedly reduce plasma estrogen levels in postmenopausal women by inhibiting the aromatase enzyme, which catalyzes the synthesis of estrogens from androgenic substances such as androstenedione. Fibroids express aromatase, and the use of aromatase inhibitors in the management of HMB due to fibroids is only confined to some case reports in which they were shown to cause a dramatic reduction in fibroid size, as well as thinning of the endometrium, leading to much lighter menstrual bleeding. A 71% reduction in fibroid size over an 8-week period has been reported by Japanese investigators .
Laparoscopic Bilateral Uterine Artery Occlusion
A 2001 study evaluating the effectiveness of laparoscopic bilateral uterine artery occlusion (LUVO) compared with UAE concluded that it was as effective as UEA, with 88.4% of patients reporting definitive symptomatic improvement and 21.2% reporting complete resolution of their symptoms . LUVO essentially involves occlusion of the uterine arteries, at the level of the internal iliac artery, with an endoclip, and coagulation of the collateral arteries between the ovaries and uterus.
Even though UAE and LUVO are known to provide symptomatic relief to patients with fibroids, they do have limitations. UAE needs to be performed by an interventional radiologist, whereas LUVO is limited by the laparoscopic expertise of the surgeon and is associated with laparoscopic complications. Consequently, alternative techniques such as the transvaginal Doppler-guided vascular clamp are being explored. The Flostat™ system (Vascular Control Systems, San Juan Capistrano, CA), is presently being used in the United States; it consists of (1) a guiding cervical tenaculum, (2) a transvaginal vascular clamp with integrated Doppler ultrasound crystals, (3) a coupler that advances the clamp over the tenaculum, and (4) a battery-powered ultrasound transceiver that generates an audible Doppler signal .
The VizAblate System (Gynesonics; Redwood City, CA) is a transcervical device consisting of an intrauterine ultrasound probe and a single-use, disposable articulating hand piece. Through intrauterine sonography, fibroids can be accurately localized, and simultaneously ablated via high RF energy delivery . The amount of therapeutic energy delivered to the fibroid relies on a fixed treatment cycle based on fibroid size. A study trial looking at the efficiency of transvaginal RF thermal ablation in treating symptomatic uterine myomas reported a 91% reduction in symptoms and a 46% improvement in overall quality of life; a 73% mean reduction in fibroid volume was also reported .
Providing a less invasive alternative to abdominal hysterectomy in the management of symptomatic fibroids, laparoscopic RF ablation involves fibroids being precisely localized via ultrasound and targeted to high RF energy through monopolar and bipolar single electrocautery needles with multiple hooked arrays. Multiprobe array RF ablation has been associated with high satisfaction rates in the management of liver, lung, and kidney tumors; spherical regions of coagulation necrosis measuring 3.5 cm have been achieved and local tumor control of up to 95% has been reported .
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