Abnormal menstrual bleeding

Essentials

  • A detailed history of menstrual bleeding is often more important than the pelvic examination.
  • Differentiate between organic and hormonal causes.
  • Differentiate between anovulatory and ovulatory bleeding.

Normal menstrual cycle

  • The average age of menarche (the first menstrual period) is 12.5 years.
  • The menstrual cycle varies from 23 to 36 days, usually from 26 to 30 days.
  • Uterine bleeding usually lasts 2–7 days, and the normal blood loss during one cycle is 25–40 ml with the upper limit of normal being 80 ml.

Associated terminology

  • Amenorrhoea
    • Absence of menstrual bleeding
      • Primary – no menstrual bleeding ever
      • Secondary – no menstrual bleeding for at least 6 months
  • Oligomenorrhoea
    • Menstrual cycle more than 36 days
  • Polymenorrhoea
    • Menstrual cycle less than 23 days
  • Menorrhagia
    • Regular bleeding, but more profuse than normally
  • Metrorrhagia
    • Irregular bleeding between periods
  • Ovulatory bleeding
    • Midcycle bleeding at the time of ovulation
  • Breakthrough bleeding
    • Bleeding at an unusual time associated with hormone therapy or hormonal contraception
  • The International Federation of Gynecology and Obstetrics (FIGO) recommends menstrual bleeding to be recorded as e.g. ”heavy regular bleeding” or ”heavy irregular prolonged bleeding”. ICD-10 classification still uses the old nomenclature.

Heavy regular bleeding (menorrhagia or hypermenorrhoea)

  • Regular ovulatory menstrual bleeding, volume > 80 ml
  • According to blood volume measurements, the prevalence among women of reproductive age is 9–14%. However, approximately one in three women suffer from excessive bleeding at some stage of their lives.
The most common causes

  • Systemic causes (5–15%)
  • Uterine causes (40–50%)
    • Polyps of the uterine cavity and submucous myomas (4)
    • Adenomyosis (Adenomyosis)
    • Copper intrauterine device (IUD)
    • Infection (6)
    • Endometrial carcinoma (the cause of menorrhagia only in about 0.1% of cases) (Gynaecological cancers).
  • Essential menorrhagia (approximately 50%)
    • No cause can be identified in an individual patient with current diagnostic methods. Caused by a multitude of mechanisms.

History

  • It is difficult, but important, to estimate the amount of blood loss. Objectively, only about half of those complaining of heavy bleeding lose more than 80 ml. Pictoral blood assessment chart (PBAC) can be used to estimate the blood loss. The patient gives herself points by comparing her own sanitary towels/tampons and blood loss/clots to pictures.
  • The patient can also be asked whether the bleeding interferes with her work and leisure time activities or sex life, does she need to use more protection now than before, does she need to change protection overnight, are there any clots, and does she feel tired or dizzy during her periods (the estimation will remain fairly rough).
  • A recent onset of symptoms may be suggestive of a uterine cause, whereas symptoms of long duration are more suggestive of a systemic cause.
  • A normal menstrual cycle length is suggestive of ovulatory bleeding, prolonged cycles to anovulatory bleeding.

Investigations

  • Pelvic examination
    • Size of the uterus, tenderness, myomas
  • Basic blood count with platelet count
    • Haemoglobin correlates fairly poorly with the amount of blood loss. If a woman complaining of menorrhagia has a haemoglobin concentration below 120 g/l, there is a probability of about 70% that the amount of menstrual bleeding is more than 80 ml per cycle. If the concentration is above 120 g/l, the probability is about 18%. If the haemoglobin concentration is below 80 g/l, refer to a specialist for further investigations.
  • Ultrasound examination (8)
    • Vaginal ultrasonography is the first-line additional investigation.
    • If there has been an essential change in the bleeding or the bleeding causes anaemia, an ultrasound examination must be performed before a treatment trial.
    • Polyps and submucous myomas are revealed in about 70% of cases.
    • Sonohysterography (9) will give more accurate information (comparable to hysteroscopy).
  • Hysteroscopy, if clear diagnosis not achieved with ultrasound examination
  • Pap smear (if not taken during the last year)
  • If necessary (only if supported by other findings)
    • Infection parameters
    • Clotting studies (von Willebrand factor activity, Ristocetin cofactor activity (vWF:Rco), clotting factor VIII)
    • TSH and free T4
    • Plasma ferritin; result < 30 µg/l indicates iron deficiency (Iron deficiency anaemia)
  • Endometrial curettage seldom gives more information.
  • Endometrial biopsy (11) should be considered to exclude malignancy if the patient has mid-cycle bleeding or other risk factors (age over 45 years, obesity: BMI ≥ 30 kg/m2 or weight > 90 kg, diabetes, thick endometrium).

Treatment

  • Treat anaemia with iron substitution .
    • An appropriate daily amount of oral iron substitution is 100–200 mg divided into 1–3 doses.
    • If required, intravenous medication
  • Systemic causes
  • Uterine causes
    • Hormone-releasing IUD [Evidence Level: A]
    • Polyps
      • Hysteroscopic polypectomy
    • Myomas (Benign gynaecological lesions and tumours)
      • Progesterone receptor modulator (ulipristal)
        • The European Medicines Agency, EMA is currently investigating a possible association between ulipristal and liver injury (see information published on the 9th of February 2018 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Es...). No new patients should be started on ulipristal and the treatment should not be continued again after the one month's pause. The liver function of women who take ulipristal should be monitored at least once a month during treatment and the treatment should be stopped if the liver enzyme levels are more than 2 times the upper limit of normal.
      • Hormone-releasing IUD may be tried [Evidence Level: D].
      • Submucous (protruding into the uterine cavity): hysteroscopic resection or morcellation by laparoscopy
      • Intramural (within the uterine muscle wall): removal by laparoscopy or, more rarely, by laparotomy
      • It is possible to use High-intensity focused ultrasound (HIFU) for treating women with symptomatic myomas or adenomyosis within specialized health care.
        • Criteria for patients suitable for HIFU treatment: premenopausal patient, subcutaneous fat layer in the lower abdomen < 5 cm, no substantial scarring on the skin of the lower abdomen, the myomas to be treated 2–10 cm in size and maximum number of myomas 2–3.
      • Embolization of the uterine arteries is an option [Evidence Level: A] that can sometimes be considered in the treatment of abnormal bleeding caused by large symptomatic myomas. Embolization may reduce bleeding and pressure symptoms by 60–90%.
      • Hysterectomy
    • Adenomyosis (endometrial tissue growing into the muscular wall of the uterus)
      • Drug therapy (see below under treatment of essential menorrhagia)
      • Endometrial ablation (in superficial adenomyosis)
      • Hysterectomy
      • HIFU (see above)
    • Removal of the copper IUD
      • Tranexamic acid or a non-steroidal anti-inflammatory drug if the patient wants to keep the IUD
  • Essential menorrhagia
    • Tranexamic acid [Evidence Level: A] 2–3 tablets (1–1.5 g) 3 times daily for 2–3 days, administered when bleeding is most heavy, will reduce bleeding by about 20–60%.
    • Non-steroidal anti-inflammatory drugs [Evidence Level: A] (not aspirin) taken at a normal dose when bleeding is most heavy will reduce bleeding by about 20–50% and alleviate menstrual pain. Remember the possibility of a haemorrhagic disorder as a contraindication.
    • Combined oral contraceptives [Evidence Level: A] reduce bleeding by 40–60%. Alleviates also menstrual pain and guarantees good contraception. Remember smoking, obesity and other risk factors.
    • A hormone-releasing IUD [Evidence Level: A] will reduce bleeding by 80–98% in more than 90% of the patients. It also alleviates menstrual pain and pre-menstrual symptoms and guarantees contraception to the level of sterilization.
    • Endometrium can be resected [Evidence Level: A] or destroyed by thermal ablation [Evidence Level: A]. The success rate is 70–97%. During a 4-year follow-up the need for further treatment is 38%. The probability of pregnancy after the intervention is low (about 1%), but the need for contraception should be considered anyhow.
    • Hysterectomy [Evidence Level: A] may be considered when drug therapy fails or cannot be used. Hysterectomy [Evidence Level: A] may be carried out transvaginally, laparoscopically or by open surgery. The patient should be informed of the need for surgery and given time for consideration.
    • Because the drugs have different mechanisms of action they can be combined, if one drug does not provide sufficient treatment response.

Evidence Summaries

Irregular uterine bleeding

  • Irregular uterine bleeding is very common. It comprises metrorrhagia, menometrorrhagia, polymenorrhoea, oligomenorrhoea, spotting, breakthrough bleeding and ovulatory bleeding. In a younger woman it is usually functional, unless she has an infection or pregnancy-related problems. The possibility of an organic cause increases with age.
Causes

  • Functional causes
    • Disturbance in the hormonal regulation of the hypothalamus, pituitary gland and ovaries
    • Luteal hormone insufficiency
    • Ovulation bleeding
  • Uterine causes
    • Problems associated with pregnancy, see (13), (14)
    • Infection, such as endometritis or salpingo-oophoritis (15)
    • Submucous myomas (16)
    • Adenomyosis, endometriosis (17)
    • Cervical and endometrial polyps (18)
    • Cervical and uterine cancers (19)
  • Other causes
    • An IUD
    • Dysfunction of the thyroid gland, hyperprolactinaemia, diabetes, obesity, systemic infection or connective tissue disease
    • Hepatic cirrhosis
    • Cardiovascular diseases that cause heart failure or venous stasis
    • Dysfunction of clotting factors or anticoagulant treatment
    • Certain drugs, such as doxycycline, metoclopramide, psychopharmaceuticals, high doses of acetosalicylic acid, spironolactone, ketoconazole, antiepileptics or antioestrogens
    • Hormonal contraception

Functional abnormal uterine bleeding

  • Ovulatory bleeding disorders
    • Young, slightly overweight girls may have frequent (< 23 days) but regular bleeding. There seems to be no hormonal disturbance and no treatment is needed.
    • Low oestrogen concentration early in the cycle may cause spotting after the menstruation.
    • Premenstrual spotting may occur due to a functional disturbance of the corpus luteum. The histological finding from an endometrial biopsy will show "irregular shedding" and "irregular ripening".
    • Some women have regular bleeding associated with ovulation. The bleeding lasts from a few hours to 1–2 days, and requires no treatment. The cause of the bleeding is the rapid decrease in the oestrogen levels after ovulation.
    • Copper IUD increases the risk of midcycle and post-coital bleeding.
  • Anovulatory bleeding disorders
    • Anovulation is the most common cause of functional bleeding disorder.
    • Typically, there is scant spotting after short cycles and prolonged, profuse bleeding after long cycles.
    • Hypothalamic disturbance is usually the causative factor of temporary anovulation in young women (e.g. excessive stress, strenuous exercise, slimming, systemic illnesses or polycystic ovaries).
    • Dysfunction of the ovaries is the usual cause after the reproductive age.
    • If the condition is prolonged it may lead to endometrial hyperplasia.
    • Polycystic ovary syndrome (PCOS, (Polycystic ovary syndrome (PCOS))) and obesity are often associated with bleeding disorders due to insulin resistance.
  • Breakthrough bleeding associated with hormonal contraception
    • Menstrual disturbances are very common during the first months with progestogen-only pills, contraceptive implants and hormone-releasing IUDs.
    • In users of combination contraceptive pills, menstrual disturbances are often due to irregular intake of the pills, but factors affecting hormone concentrations and the functioning of the endometrium are also possible causes.

Diagnosis and examination

  • Careful history and physical examination are most important.
  • The choice of diagnostic methods is dependent on the patient's age and history.
    • Exclude pregnancy and infection.
      • Pregnancy test either from the urine or blood
      • Swabs for infection tests (Chlamydia, gonorrhoea if necessary), CRP and basic blood count with platelets
    • Vaginal ultrasound (21) should be carried out on all patients if feasible. Very accurate in the diagnosis of submucous myomas, endometrial polyps and endometrial hyperplasia but does not substitute an endometrial biopsy (22).
      • Infusion of saline solution into the uterine cavity enhances the accuracy of ultrasonography.
    • Endometrial biopsy should be obtained from older women (> 45 years) (23) particularly if there are risk factors for uterine cancer (24) (age, obesity, diabetes (Gynaecological cancers)).
    • Pap smear if not taken within the last 12 months
    • Hysteroscopy if diagnosis remains unclear after the ultrasound examination or if an endometrial biopsy is required of a particular area.
    • Laboratory tests as required: TSH, prolactin, clotting factor studies

Treatment of dysfunctional bleeding

  • If no organic cause has been found to explain the abnormal bleeding and the symptoms are transient, no treatment is needed.
  • The IUD may be removed (remember contraception) or if the patient so wishes a watchful wait may be instigated, provided that no organic cause has been identified.
  • Bleeding can usually be stopped with progestogens, the most suitable ones being norethisterone (5 mg three times daily), norethisterone acetate (10 mg twice daily) and lynesterol (10 mg twice daily). They should be administered for 10 days. After stopping the medication the patient will have withdrawal bleeding (inform the patient). In most cases it is advisable to continue the progestogen treatment in a cyclic manner and using a smaller dose for a period of 3 months.
  • An effective alternative for long-term treatment is a hormone-releasing IUD [Evidence Level: A]. When the growth of the endometrium is prevented, the amount of bleeding and the number of bleeding days decrease, menstrual pain is relieved and at the same time contraception is guaranteed with the same efficacy as with sterilization.
  • Oestrogen and progestogen given together for 7–14 days is the most effective way to stop hormonal bleeding at the extreme ends of reproductive age. Oral contraceptives (monophasic) 3 tablets per day for one week should be prescribed for young women. If the patient feels unwell the dose should be reduced. Estradiol valerate 2 mg daily, combined with a progestogen, should be prescribed for older women and for those who have contraindications for synthetic oestrogen. A withdrawal bleeding will follow after the medication is stopped. If the withdrawal bleeding is profuse it can be treated with a prostaglandin inhibitor or tranexamic acid.
    • The daily administration of oral contraceptives is introduced according to the packet instructions. Otherwise, the treatment of functional bleeding is continued with cyclical progestogen on days 15–24 of the cycle for 3–6 months using lower doses.
  • The bleeding disorder in women with a hereditary haemorrhagic disease (mild and in some cases moderately severe von Willebrand's disease, carriers of haemophilia A) may be treated with desmopressin. The drug is administered subcutaneously or as an intranasal spray (one dose of 150 µg per day during the bleeding disorder for women weighing less than 50 kg and two doses if the weight is over 50 kg).
  • If the irregular bleeding is profuse, tranexamic acid (1–1.5 g t.i.d.) [Evidence Level: A] or an NSAID (e.g. ibuprofen 400–600 mg t.i.d.) [Evidence Level: A] may be given.
  • Endometrial curettage is not usually needed. Endometrial hyperplasia as a result of anovulatory states requires curettage, if bleeding is profuse and anaemizing. In other case, cyclic progestogen or a hormone-releasing IUD is used for 6 months, and endometrial biopsy is controlled thereafter by a pipelle. If the endometrial sample is inadequate or it cannot be obtained, a hysteroscopy is better than curettage. Polyps and submucous fibroids should be removed hysteroscopically.

References

1. Larsson G, Milsom I, Lindstedt G, Rybo G. The influence of a low-dose combined oral contraceptive on menstrual blood loss and iron status. Contraception 1992 Oct;46(4):327-34.  [PMID:1486771]

2. Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol 1995 Jun;85(6):977-82.  [PMID:7770270]

3. Fraser IS, Critchley HO, Broder M et al. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Semin Reprod Med 2011;29(5):383-90.  [PMID:22065325] http://www.medscape.com/viewarticle/753127


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