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Abstract

Abnormal uterine bleeding imposes major medical, social and financial problems for women, their families and the health services. Abnormal uterine bleeding refers to the regularity, frequency, duration and volume of bleeding. Irregular menstrual bleeding is most common at the extremes of reproductive life, in the initial 12–18 months after menarche and 5–6 years before the menopause begins. In Australia, the estimated cost of investigating and managing heavy menstrual bleeding alone is approximately AUS $6 million per annum. This article addresses the common causes of irregular bleeding in pre- and peri-menopausal women and presents an investigational approach.

Keywords

abnormal uterine bleeding adolescents dysfunctional uterine bleeding hormonal therapy menstrual irregularities oral contraceptive pill perimenopausal polycystic ovarian syndrome progestogens reproductive age

Abnormal uterine bleeding (AUB) is that which is irregular, heavy and/or prolonged [1]. Disturbances of menstrual bleeding are a major medical, social and financial problem for women, their families and the health services. In many developed countries, AUB is the most common reason for women to consult their general practitioner or gynecologist and is responsible for as many as a third of all outpatient visits to a gynecologist [2]. A total of 40% of British women believe their bleeding to be ‘excessive or heavier than usual’ and 10% complain of prolonged bleeding [3]. This translates into nearly 4 million Australian women. Irregular menstrual bleeding is most common at the extremes of reproductive life, in the initial 12–18 months after menarche and 5–6 years before the menopause begins [4].

In Australia, the estimated cost of investigating and managing heavy menstrual bleeding alone is approximately AUS $6 million per annum [1]. AUB refers to the regularity, duration and volume of vaginal bleeding [5]. The causes of AUB are poorly understood and this has considerably limited the development of medical treatment options. Approximately 35% of Australian women eventually undergo hysterectomy, which represents a major additional health cost, the majority for menstrual disorders [6].

A confusing, inconsistent and overlapping array of terms has evolved to describe abnormal frequency, duration or volume of uterine bleeding [5]. For this reason, the general term ‘abnormal uterine bleeding’ is often used instead of terms such as polymenorrhea, menorrhagia and oligomenorrhea. Dysfunctional uterine bleeding (DUB) is not a generic term for AUB, but is excessively heavy, prolonged or frequent bleeding of uterine origin that is not due to pregnancy or to recognizable pelvic or systemic disease.

Normal menstrual cycle

The normal menstrual cycle results from a complex feedback system involving the hypothalamus, pituitary, ovary and uterus. The key aspects of menstruation that may be altered in AUB include [5]:

Cycle regularity: irregular, regular or absent

Frequency of menstruation: frequent, normal or infrequent

Duration of menstrual flow: prolonged, normal or shortened

Volume of menstrual flow: heavy, normal or light.

Large population studies have defined the normal range of menstrual cycle length, duration of bleeding and amount of blood loss [4]. The average adult menstrual cycle is 28 days, with a range between 21 and 35 days, 4–6 days of flow and median blood loss of 30 ml, with 80 ml as the upper limit of normal [1].

This article will address common causes of irregular bleeding in pre- and peri-menopausal women and will present an investigational approach. Bleeding that is too frequent (a cycle of less than every 21 days) or infrequent (a cycle of more than every 36 days) will be discussed. Pregnancy-related bleeding, primary and secondary amenorrhea, and investigation and causes of heavy menstrual bleeding are beyond the scope of this article.

Causes of menstrual irregularities in adolescents: less than 20 years old

Irregular uterine bleeding in adolescent girls may result from a wide spectrum of conditions including structural and endocrine causes, and DUB. Pregnancy should always be excluded as a cause. The most common cause is anovulation, which may be due to immaturity of the hypothalamic–pituitary–ovarian (HPO) axis (causing anovulatory DUB) or polycystic ovary syndrome (PCOS).

In the initial months following menarche, the normal negative feedback system between the ovaries and anterior pituitary may malfunction. If increasing levels of estrogen do not cause a decrease in follicle-stimulating hormone (FSH) secretion with subsequent suppression of estrogen secretion, multiple follicular recruitment is stimulated and a dominant follicle does not form. Under the influence of continued estrogen secretion, the endometrium becomes excessively thickened and, without adequate progesterone levels, may slough, leading to heavy and irregular bleeding. The heavy bleeding may be worsened by an increase in prostacyclin synthesis in endometrial capillary epithelial cells under the influence of estrogen in the absence of progesterone. This is because even an occasional ovulatory period stabilizes and coordinates the sloughing of the endometrium [7 –9]. By definition, other causes of irregular menses must be excluded before a diagnosis of DUB can be made.

A common cause of chronic anovulation in adolescents is PCOS, which should be considered in any adolescent with menstrual irregularity, clinical hyperandrogenism (hirsutism or acne) or obesity. PCOS should also be considered in adolescents who continue to have menstrual irregularity 3–4 years after menarche, even in the absence of hirsutism or acne [9]. PCOS is diagnosed in the presence of two out of three of the following: polycystic ovary appearance on ultrasound, clinical or biochemical hyperandrogenism and anovulation [10]. The diagnosis of PCOS in adolescence is problematic since many clinical features (e.g., menstrual irregularity and acne) are considered ‘normal’ in adolescents. It was previously considered that adolescent menstrual irregularity represents normal maturation of the HPO axis. However, there is increasing evidence that this is not the case and that persistent menstrual irregularity in adolescence may be an early presentation of PCOS. Menstrual irregularity associated with normal reproductive development is likely to resolve within the first 2 years following menarche [11]. After this time, over 70% of adolescents with irregular menses have clinical and metabolic signs of PCOS [12]. By contrast, adolescents aged 15 years with regular cycles rarely develop menstrual irregularity in adulthood. Prospective cohort studies demonstrate that the majority of adolescents with menstrual irregularity continue to have irregular menses as adults, particularly those with a high BMI [13] or persistent acne vulgaris [11]. Furthermore, menstrual irregularity in adolescents is commonly associated with clinical, endocrine and ultrasound signs of PCOS [13]. The population incidence of PCOS in adolescence is not known, but these studies suggest that it may be common and is likely to be underdiagnosed. However, there is increasing evidence that early diagnosis of PCOS may confer clinical advantages. Other endocrine causes of anovulation including thyroid dysfunction and hyperprolatinemia should be ruled out. If clinically indicated, adrenal gland abnormalities, such as Addison disease, late-onset congenital adrenal hyperplasia or Cushing disease, may need to be excluded [9,14,15].

Significant weight loss, stress and exercise can disturb the HPO axis and are not uncommon causes of oligo/anovulation.

In those who are sexually active, endocervical or pelvic infection may present with irregular vaginal bleeding [16].

Evaluation

The evaluation of the adolescent with AUB begins with a careful history and physical examination. The physical examination further helps to narrow the differential diagnosis and to direct subsequent laboratory or radiographic evaluation.

History

The patient's history should be obtained with and without the patient's guardian in the room. Some girls prefer to be interviewed alone, particularly if they have been sexually active. Speaking with the patient alone, and with her guardian present, facilitates obtaining a thorough history and maintains the patient's confidentiality on subjects that she may not be comfortable discussing in front of her parents.

A thorough menstrual history is critical for the evaluation of patients with abnormal vaginal bleeding. This includes the age of menarche; the characteristics of the first menstrual period; the general frequency of periods; whether periods have ever been regular; any associated dysmenorrhoea; the timing, duration and quantity of bleeding during recent menstrual cycles; and/or abnormal bleeding episodes. In girls who describe a change in the menstrual pattern, it is important to ask about other events that coincided with the change, such as stress, weight loss or an increase in exercise levels. In patients with irregular cycles, maintaining a menstrual calendar is very useful [17]. Patients should be asked regarding any discharge from the breasts.

The sexual history should include information regarding contraception and condom use; number of partners; new partners; history of sexually transmitted infections or current symptoms (e.g., vaginal discharge and pelvic pain); previous pregnancies or terminations; whether sexual activity was forced or consensual; and whether the adolescent has a history of sexual abuse [18].

The medical history should include information regarding systemic illness, hematologic or renal disease, and current or recent medications. The doctor should enquire about weight change, exercise regimens, substance use, hirsutism, acne, visual changes and headaches.

A history of menstrual disorders in the family may suggest PCOS, or other familial endocrine disorders.

Examination

The general examination should include: vital signs, including pulse and blood pressure levels [9,18,19]; measurement of height and weight and calculation of BMI; palpation of the thyroid gland for enlargement or other abnormalities. Evaluation for signs of androgen excess includes hirsutism, acne, male pattern balding and signs of acanthosis nigricans. If the prolactin is elevated the optic fundi should be examined and visual field tested to evaluate the possibility of a pituitary tumor. Tanner staging of the breasts and assessment for galactorrheoa (bilateral milky nipple discharge) should be conducted as well as palpation of the abdomen for uterine or ovarian mass.

As part of a secondary care approach, an examination of the external genitalia should be carried out whenever indicated. It is also important to look for nonuterine sources of bleeding (e.g., perineal trauma, vulvar lesions and signs of sexually transmitted infections). Girls who have signs of perineal trauma should be questioned privately regarding sexual abuse.

Pelvic examination

When indicated, a speculum examination should be performed in order to rule out the possibility of bleeding ectropion. A bimanual examination is performed to assess for ovarian or uterine masses and signs of pelvic inflammatory disease. If the history or symptoms suggest pelvic infection, microbiological specimens should be collected from the cervix and vagina. All girls who are sexually active should have a Pap smear as per the national cervical screening policy.

Laboratory evaluation

This should include a pregnancy test, a complete blood count and measurement of thyroid-stimulating hormone and prolactin levels. Blood should be obtained during the early follicular phase (days 2–6 of cycle) to test for PCOS. This includes FSH, luteinizing hormone (LH), estradiol, total and free testosterone levels, dehydroepiandrosterone sulfate (DHEAS) levels, sex hormone-binding globulin, fasting lipid profile, fasting plasma glucose level, 17 α-hydroxypro-gesterone (elevated in late-onset congenital adrenal hyperplasia), fasting insulin level, and, if indicated, urinary free cortisol to rule out Cushing's syndrome. In those with raised FSH, karyotype should be carried out [20,21].

Pelvic ultrasound

Pelvic ultrasound is indicated in all women, transabdominal ultrasound is less sensitive and specific than transvaginal ultrasound; however, with optimum conditions may still be helpful. Pelvic ultrasound may also indicate uterine structural abnormalities and assist in the diagnosis of PCOS [21].

Management

The principal goals in managing irregular uterine bleeding in adolescence are [17,22]:

Make the diagnosis

Correction of acute or chronic anemia

Return to a pattern of normal menstrual cycles

Prevention of recurrence

Prevention of long-term consequences of anovulation

For those with anovulatory DUB, the primary purpose of treatment is to stabilize endometrial proliferation and promote regular shedding. All patients with DUB are at risk for iron deficiency anemia and should be monitored and treated accordingly. The decision of whether to observe girls with DUB or to treat them with hormonal therapy depends upon patient and guardian considerations, as well as upon the severity and chronicity of the DUB. Cyclic progestogens or oral contraceptive pills (OCP) may restore regular bleeding patterns [17,19]. More than 90% of adolescents with DUB respond to hormonal therapy [23,24]. Among those who do not, an alternative diagnosis (e.g., bleeding disorder, PCOS, infection and uterine pathology) should be considered.

The treatment of DUB is guided by both the hemoglobin level and whether the patient is actively bleeding ( Table 1 ) [8,17].

Table 1.

Treatment of dysfunctional uterine bleeding.

Hemoglobin level	Treatment of dysfunctional uterine bleeding	Ref.
Hemoglobin level is greater than 12 gm/dl and patient is not actively bleeding	• Reassurance
	• Maintain a menstrual calendar
	• Iron supplementation and re-evaluated in 3–6 months
Hemoglobin level is between 10 and 12 gm/dl	• Hormone therapy	[29]
	• Iron supplementation
	• Hormone therapy is often a estrogen–progestin OCP. If the patient is unable or unwilling to take daily OCPs and is not sexually active, an alternative is to use intermittent oral medroxyprogesterone acetate or norethindrone acetate, 10 mg daily for 10–14 days every month or any other progestogens with equivalent doses for three to six cycles. Cyclic oral progesterone administered for 10 days each month prevent the actions of unopposed estrogen and stabilize the endometrium. Withdrawal of progesterone each month allows organized sloughing of the endometrium and clinically leads to predictable menses during the perimenarchal, anovulatory period.
	• Re-evaluate at 3 months or earlier if needed
Hemoglobin level is less than 10 gm/dl and patient is asymptomatic and not actively bleeding	• Estrogen-progestin OCP is indicated, together with iron supplementation. Patients who have complaints of heavy bleeding may have a better response to OCP that have a combination of estrogen and progestin rather than to progestin-only preparations, since estrogen provides hemostasis. Monophasic OCPs (i.e., pills that contain the same dose of estrogen and progestin in each of the hormonally active pills) with a minimum of 30 μg ethinyl estradiol should be used in order to ensure a sufficient amount of estrogen is provided to prevent breakthrough bleeding.

Treatment of dysfunctional uterine bleeding is guided by both hemoglobin levels and whether the patient is actively bleeding.

OCP: Oral contraceptive pill.

All patients with PCOS should be managed with supportive therapy that encourages lifestyle changes, the maintenance of a healthy weight, exercise and diet. Menstrual irregularity should be treated in patients with PCOS, since chronic anovulation is associated with increased risk of developing endometrial hyperplasia and carcinoma. The major treatment options for menstrual irregularity include progestin or OCPs. Treatment of adolescents with PCOS using oral hypoglycemics improves key clinical and metabolic parameters, including hyperandrogenemia, insulin resistance, dyslipidemia and obesity [25 –27].

Oral contraceptive pills are the first-line endocrine treatment for women with the dermatologic or menstrual abnormalities of PCOS [28]. OCPs induce regular menstrual periods with a higher degree of reliability than any other form of treatment. Progestin inhibits endometrial proliferation, preventing hyperplasia. Estrogen inhibits the activity of the hypothalamic–pituatary–gonadal axis, reducing ovarian androgen production as well as increasing the sex hormone-binding globulin levels. OCP therapy normalizes the androgen levels in most cases within 18 to 21 days. There are many choices of OCP, and it is recommended to use one that has a progestin with antiandrogenic or minimal androgenic activity. Menstrual irregularities in PCOS can often be treated effectively with micronized progesterone, 100–200 mg daily at night for 7–10 days [29]. This induces withdrawal bleeding in most patients; however, some do not respond, apparently because of an antiestrogenic effect of androgen excess on the endometrium [30]. Progestin therapy has the appeal of permitting the detection of the emergence of normal menstrual cyclicity. The perimenarcheal girl who responds well to progestin therapy can be maintained at approximately 6-week cycles to permit the detection of spontaneous menses. Patients must be informed that oral progestin dosed in this way is not a means of contraception [20].

Controversy persists regarding the use of oral contraceptives in women with PCOS. OCPs provide cycle control, ameliorate androgenic symptoms and protect the endometrium. Nevertheless, there are several potential disadvantages to the use of OCPs for managing PCOS in adolescents. In perimenarcheal girls with short stature who have open epiphysis, OCPs are contraindicated because they contain growth inhibitory amounts of estrogen. OCPs may also be contraindicated in patients who are at risk for venous thrombosis. Patients may use OCPs as an excuse for not losing weight. The patient may believe that the treatment is curative and defer a definitive diagnostic work-up. In addition, OCPs do not permit conception if and when it is desired. The long-term consequences of these agents on fertility is unknown; concerns have been raised that the immature adolescent neuroendocrine system may have heightened the risk for postpill amenorrhea and infertility when exposed to high-dose estrogen in early adolescence [31,32]. However, this concern is based on observations in other patient groups undergoing treatment with high-dose estrogens during adolescence, and its relevance to girls in PCOS in unclear. Regarding PCOS, there are also some concerns that the abnormal cardiovascular and metabolic profiles commonly observed with PCOS may be exacerbated by the OCP. Estrogens impair carbohydrate tolerance, dose-dependently, as do androgens and progestins of greater androgenicity. The composite effect of OCPs on glucose tolerance and insulin sensitivity is determined by the interplay of the above actions with the insulin sensitivity of the individual, itself determined genetically, environmentally, as well as by other factors such as puberty. The environmental influence may vary over time. OCPs increase HDL and triglycerides, and this effect varies with the progestin. Thus, in some PCOS patients, such as the obese or pubertal, this additional metabolic risk should be considered when OCPs are prescribed, and appropriate surveillance is advisable, as is concomitant use of agents that modify these effects, such as metformin or choosing the OCP mainly containing progestins with antiandrogenic properties [33].

Duration of therapy & follow-up

Girls treated with progestin therapy or combined hormonal contraceptives should return for follow-up in 3 months. As a general rule, OCP treatment should be continued until the patient is gynecologically mature (5 years postmenarchal) or has lost a substantial amount of excess weight. At that point, withholding treatment for a few months to allow recovery of suppression of pituitary–gonadal function and to ascertain whether the menstrual abnormality persists is usually advisable [29]. A menstrual calendar should be maintained to monitor subsequent episodes of irregular bleeding.

Long-term follow-up of girls with a history of anovulatory cycles is essential. Chronic anovulation (greater than 2–3 years in duration) is associated with an increased risk of endometrial hyperplasia and carcinoma, particularly if the patient is obese or has a family history of endometrial, ovarian, breast or colon cancer. Obesity promotes peripheral conversion of androgens to estrogens, further enhancing endometrial growth [34,35].

Causes of menstrual irregularities in the reproductive age group: 20–40 years

Spontaneous irregular uterine bleeding is relatively uncommon in women who have previously had regular cycles. Pregnancy should be considered as a cause in any sexually active women of reproductive age. Women who are pregnant are evaluated primarily for pregnancy-related causes of bleeding; however, the possibility of a concurrent nonpregnancy-related etiology should be kept in mind.

Polycystic ovary syndrome causes irregular uterine bleeding in reproductive-aged women, affecting approximately 6% of women in this group [36]. Women with PCOS are adequately estrogenized, since androgens can be converted peripherally to estrogens even in the absence of normal ovarian function, but low levels of progesterone. Thus, constant mitogenic stimulation of the endometrium leads to endometrial hyperplasia and unscheduled bleeding.

Endocrine disorders may be associated with hormonal changes that affect ovulation and cause irregular menstruation. Both hypo- and hyper-thyroid activity are associated with AUB. Women with hypothyroidism, even when subclinical, may have heavy or prolonged uterine bleeding [37]. Hypothyroidism can cause hyperprolactinemia; this usually results in amenorrhea and galactorrhea, but women may develop irregular menstrual bleeding prior to amenorrhea. Hyperthyroidism may cause anovulation and irregular menstruation owing to alterations in sex hormone-binding globulin [38].

Cushing's syndrome is a rare cause of menstrual irregularity [39]. Menstrual abnormalities correlate with increased serum cortisol and decreased serum estradiol concentrations, but not with serum androgen concentrations. The menstrual irregularities may be due to suppression of secretion of gonadotropin-releasing hormone by hypercortisolemia. High doses of corticosteroids have a similar effect.

Hormone-secreting adrenal and ovarian tumors are rare causes of menstrual irregularities. The level or activity of sex hormones may be affected by disorders unrelated to endocrine glands, such as advanced liver or renal disease, that alter hormone metabolism or binding or suppress ovulation and lead to menstrual irregularities. Liver disease can affect both estrogen metabolism and synthesis of coagulation factors, thereby potentially leading to both anovulation and bleeding diathesis; in additon, chronic renal disease is associated with both hypothalamic–pituitary–gonadal and platelet dysfunction leading to characteristic noncyclic bleeding pattern.

Stress, significant weight loss and exercise can disturb the HPO axis and are not uncommon causes of irregular menstruation. Uterine polyps are usually benign endometrial growths of unknown etiology. Irregular bleeding is the most frequent symptom, occurring in approximately 50% of symptomatic cases. Leiomyomas, also known as fibroids, are the most common pelvic tumors in women, occurring in approximately 25% of women of reproductive age. Intramural and submucosal fibroids distort the endometrial cavity, resulting in unusually heavy or prolonged menstrual periods but those that form polyps may present with irregular bleeding.

Reproductive-aged women with chronic endometritis may present with AUB. Vague, crampy lower abdominal pain may accompany the bleeding. The most common finding on physical examination is uterine tenderness or cervical motion tenderness.

Evaluation

The foundation of the evaluation of patients with AUB is the history, the physical examination and the pelvic examination. Based on the history and examination appropriate investigations can be directed.

History

The patient's history includes the onset, frequency, duration and the severity of the bleeding, changes from the usual menstrual pattern and whether the bleeding is associated with pain. Irregular bleeding needs to be distinguished from intermenstrual bleeding; intermenstrual bleeding is characterized by somewhat of a cycle and bleeds in between while irregular bleeding has a completely random pattern. Irregular heavy periods are characteristic of anovulatory bleeding. Age, parity, marital status, sexual history, previous gynecologic disease, contraceptive history, medications and the dates of all past pregnancies are all relevant to the evaluation of women with AUB. Symptoms of pregnancy and those related to reproductive tract disease are important. Weight gain, marked fatigue, cold hands and feet, constipation, failure to perspire in warm weather and a goiter are symptoms and signs indicating that hypothyroidism may be present. A history of liver disease, excessive alcohol consumption, jaundice, hepatomegaly, spider hemangiomata, palmar erythema and ascites are found in cases of advanced liver disease.

Symptoms of lower abdominal or pelvic pain, fever, chills, shakes and a purulent discharge suggest the presence of infection.

Examination

A general examination should be performed to look for signs of systemic illness such as fever, ecchymoses, an enlarged thyroid gland or evidence of hyperandrogenism (e.g., hirsutism, acne, clitoromegaly or male pattern balding). Acanthosis nigricans is highly suggestive of insulin resistance. Galactorrhea may occur with hyperprolactinemia.

Physical examination of the external and internal anatomy of the female genital tract is crucial in identifying anatomic causes of AUB. The physician should assess the size, contour, and tenderness of the uterus. An enlarged uterus with an irregular contour caused by discrete, firm tumor masses are findings of a fibroid uterus and physical findings of uterine or adnexal pain on palpation or movement of the pelvic organs, a sensation of increased warmth of the uterine and adnexal structures, and purulent cervical discharge is suggestive of pelvic infection.

Laboratory evaluation

A complete blood cell count is obtained from all patients to check for anemia and platelet count to rule out thrombocytopenia. Pregnancy should be excluded – modern urinary pregnancy tests are highly sensitive [40].

Assessment of cervical cytology (e.g., conventional or liquid based) should be performed as per the national cervical screening guidelines or if the cervical appearance is abnormal. After pregnancy has been excluded as a cause, an endometrial biopsy should be performed in all women over 45 years of age to rule out endometrial cancer or a premalignant lesion (e.g., endometrial hyperplasia) [11]. Endometrial biopsy may be considered in younger women who have risk factors for endometrial cancer: family or personal history of ovarian, breast, colon or endometrial cancer; tamoxifen use; chronic anovulation; obesity; estrogen therapy; prior endometrial hyperplasia; and diabetes [13].

All women with irregular bleeding and in the presence of clinical features suggestive of hypo- or hyper-thyroidism have thyroid function tests. Thyroid-stimulating hormone is elevated in hypothyroidism and subnormal in hyperthyroidism. Testing for Neisseria gonorrhea and Chlamydia trachomatis should be performed in patients at risk with intermenstrual or postcoital bleeding or if there is cervicitis, purulent vaginal discharge and/or pelvic tenderness. The vaginal discharge should also be evaluated for trichomonads.

A prolactin level should be measured in all women with irregular bleeding. Tests for PCOS should be conducted, as well as tests to rule out other endocrine disorders, which include FSH, LH, estradiol, total and free testosterone levels, DHEAS levels, sex hormone-binding globulin, fasting lipid profile, fasting plasma glucose level, 17 α-hydroxyprogesterone (elevated in late-onset congenital adrenal hyperplasia), fasting insulin level, and if indicated, urinary free cortisol to rule out Cushing's syndrome.

If the history and physical examination identify specific individuals with AUB who are at high risk for liver disease, liver function tests should be obtained.

Pelvic ultrasound

The use of transvaginal ultrasonography of the pelvis allows for the detection of gross pelvic pathology and uterine fibroids. Ultrasound can also assess endometrial thickness and characterize ovarian masses. In premenopausal women, the examination should be performed on day 4, 5 or 6 of the bleeding cycle, when the endometrium is expected to be its thinnest (in reproductive-aged women, normal endometrial thickness in the proliferative phase is 4–8 mm and in the secretory phase 8–14 mm [41]. This allows better visualization of pathology in the uterine cavity. If structural abnormalities are suspected on ultrasound examination, then these abnormalities can be further evaluated by saline infusion sonography or hysteroscopy.

Management

The management of AUB depends on the etiology of the bleeding. In patients with identifiable causes, treatment is targeted toward the cause [42].

Cervical polyps can be removed in outpatient clinic and endometrial polyps are removed surgically by operative hysteroscopy. Symptomatic uterine myomas are excised by operative hysteroscopy, myomectomy or hysterectomy. Infections are treated with antibiotics that cover the specific microorganisms involved.

The treatment of endometrial hyperplasia depends on whether atypia is present or absent and whether the hyperplasia is simple or complex as well as on the patient's fertility plans. Management of hyperplasia is not discussed in this article.

Underlying systemic disorders and endocrine disorders need specific treatments. Once they are treated the AUB is corrected.

Dysfunctional uterine bleeding is a diagnosis of exclusion. The objectives of treating patients with DUB are:

To control the bleeding

To prevent recurrences

To preserve fertility

To correct associated disorders

To induce ovulation in women who desire to conceive

The age of the patient, the severity of the bleeding, her number of children, the desire for future fertility and the presence of associated pelvic pathologic disorders, are factors that influence the selection of therapy. Acute bleeding episodes can be managed with high-dose estrogen–progestin therapy. To prevent recurrent episodes of anovulatory DUB, many physicians consider progestin therapy as the preferred treatment. Progestins stop endometrial growth and support and organize an estrogen-primed endometrium. When progestin therapy is withdrawn, an organized slough to the basalis layer of the endometrium occurs, which permits a rapid cessation of the bleeding when there is adequate endogenous estrogen. A recent Cochrane review has indicated that there was insufficient evidence to demonstrate the effect of either progestogen alone or in combination with estrogens for DUB [43].

In women with PCOS, treatment depends upon the woman's goals. In obese women, some of the manifestations of PCOS can be ameliorated by weight loss. The desire for pregnancy in the near future is also a major determinant for choice of therapy. In women not desiring a pregnancy, oral contraceptives are most commonly used for endometrial protection, since they also provide contraception and cosmetic benefit. The choice of oral contraceptive is important because many progestins also possess androgenic effects. Contraceptives containing nonandrogenic progestins are preferred [44 –46]. Drospirenone, an analogue of spironolactone with unique antimineralocorticoid and antiandrogenic activities, is available for use in combination with ethinyl estradiol, thus improving the antiandrogenic activity of an oral contraceptive for women who have PCOS [47]. A recent meta-analysis demonstrated a twofold increased risk of myocardial infarction and ischemic stroke in subjects taking low-dose oral contraceptives when compared with nonoral contraceptive users [48,49]. However, there is a controversy regarding the influence of OCP on insulin metabolism as there have been several reports that insulin sensitivity have been improved or not modified by OCPs that mainly contain progestins with antiandrogenic property [50,51]. If insulin resistance deteriorates in some PCOS patients with the use of oral contraceptives, metformin may be an option in the treatment regimen. For women with PCOS who choose not to or cannot take OCPs, an alternative treatment for endometrial protection is intermittent progestin therapy. Women with PCOS who want to become pregnant require further investigations and management of subfertility, which is beyond the scope of this article.

Menstrual irregularities in perimenopausal women: older than 40 years

Causes

Menstrual bleeding irregularities are a hallmark of the menopausal transition but frequently result in women seeking gynecologic consultation [52]. Menopausal transition is a phase of menstrual life when a persistent increase in variation between menstrual intervals occurs and starts at approximately 40 years of age across the population. The median age at onset of transition is 45.5 years, with a median duration of 4.8 years [4]. Although an overwhelmingly probable marker of the normal transition, bleeding irregularity raises concerns regarding possible pregnancy, endometrial hyperplasia, or gynecologic malignancy and leads to diagnostic and therapeutic interventions. Several longitudinal studies have demonstrated that menstrual cycles become more irregular in the years preceeding the final menstrual period.

Anovulation is associated with both short- and long-cycle intervals as well as with both short and long duration of the ensuing menstrual period. However, anovulatory cycles were observed only after entry into early transition, which may thus provide an indication of the occurrence of abnormal ovarian function, resulting from the reduction in ovarian follicle number. The irregularity may result from changes in the endocrinology of ovulatory cycles, or from the progressively increasing occurrence of anovulatory cycles. A total of 20% of cycles were found to be anovulatory in this group of women, predominantly in the early perimenopause. Short-cycle intervals are more often observed early in the menopausal transition. Thus, short intervals may be the first sign of a woman entering the transition; longer cycle intervals are observed later and are associated with higher FSH production, indicating even fewer functioning ovarian follicles [53,54].

Pregnancy should be considered in any female with AUB even in perimenopausal age. Uterine polyps are usually benign endometrial growths of unknown etiology that are a common cause of AUB in perimenopausal women, particularly among tamoxifen users in whom the incidence of endometrial polyps is approximately 32% [55].

Thyroid function should also be investigated since a low thyroid hormone level is more likely to be associated with infrequent menses. In women, there is an overall incidence of hypothyroidism of approximately between 6 and 4% in the perimenopausal age range [14].

Abnormal perimenopausal bleeding is associated with endometrial carcinoma in approximately 10% of cases; however, the highest risk of endometrial carcinoma is among women who weigh greater than or equal to 90 kg and who are 45 years or older [56].

Evaluation

The key to the diagnosis of AUB in perimenopausal women is a thorough history, physical examination and pelvic examination directed at all possible components of the differential diagnosis. In general, it is a mistake to use any hormonal therapy to slow or stop the bleeding until cancer of the endometrium has been eliminated as a possible cause. The development of flexible suction catheters for office endometrial biopsy has greatly facilitated the detection of endometrial hyperplasia, atypia and cancer; however, unfortunately, we often only find what we look for. The best way to detect endometrial cancer is to consider it when making a diagnosis. Irregular cycles in the late transition period or menopause without vasomotor symptoms should be investigated [57]. The recommendation regarding investigation of AUB from the Royal College of Obstetricians and Gynaecologists is that women over the age of 45 years should be investigated with hysteroscopy and endometrial biopsy [17].

Endometrial biopsy

Outpatient endometrial sampling can be performed in perimenopausal women presenting with irregular bleeding. The reported sensitivity for detecting endometrial abnormality is approximately 85% with endometrial sampling [19,23,58]; however, hysteroscopy with selective biopsy is more appropriate.

Transvaginal ultrasonography is useful in determining endometrial thickness and morphology as well as the regularity of the endo–myometrial border. Whilst the procedure is well tolerated by patients, sessile or pedunculated lesions of the endometrium and malignant disease cannot be definitively excluded [24]. Vaginal sonohysterography is a modification of vaginal ultrasound in which a small volume (5–15 ml) of saline is injected into the uterine cavity during ultrasound examination. This enables irregularities of the endo–myometrial border and the free endometrial border to be more easily visualized [59,60]. With regard to diagnostics of the uterine cavity, recently a meta-analysis on the accuracy of saline infusion sonography in women with AUB reported a sensitivity and specificity of 0.95 and 0.88, respectively [61].

Hysteroscopy

Hysteroscopy is considered an accurate gold standard in uterine cavity evaluation. Hysteroscopy allows the operator to view the entire cavity and take a directed biopsy. It is more specific and sensitive than transvaginal ultrasound or blind endometrial sampling [62]. In order to achieve optimal visualization it is practical to schedule diagnostic hysteroscopy in the follicular phase of the cycle. It is both feasible and highly acceptable in the majority of patients, giving a high detection rate for intrauterine pathology. The prevalence of intrauterine abnormalities in women with AUB is approximately 46% at the time of hysteroscopy from a recent meta-analysis. This meta-analysis also indicates that diagnostic hysteroscopy has a sensitivity and specificity of 0.94 and 0.89, respectively [63].

Management

A stepwise evidence-based approach to managing irregular bleeding is recommended. Anovulatory irregular bleeding requires endometrial protection with a combined OCP (COCP), the levonorgestrel intrauterine system (LNG-IUS) or cyclic oral progestins. Oral contraceptives, especially the low-dose types, often represent the best option to manage women presenting with vasomotor symptoms in the late transition period. They induce regularity of cycles and control hot flushes [57].

The LNG-IUS (Mirena, Bayer Schering Pharma, Berlin, Germany) is a relatively new treatment for AUB that remains effective for 5 years. It has been found to reduce menstrual blood loss by 74–97%, and approximately 50% of women will be amenorrheic by 12 months [64,65]. Some studies have described the use of the LNG-IUS among women in the late phase of the menopausal transition, including those with irregular menstrual cycles and vasomotor symptoms. The LNG-IUS with estrogen supplementation in perimenopausal women suppresses endometrial proliferation resulting in amenorrhea and relieves vasomotor symptoms. The use of the LNG-IUS in perimenopausal women seems to be well tolerated and associated with a favorable bleeding pattern [66]. The LNG-IUS is an off-label treatment used for menstrual bleeding in the USA.

If polyps are the cause of irregular bleeding they should be removed at hysteroscopy in order to exclude hyperplasia or malignancy. This may improve abnormal bleeding; however, this has not been well studied. Endometrial polyps may recur.

In cases in which irregular bleeding does not respond to medical or more conservative measures, or in cases in which women have completed childbearing, surgery is an option.

Endometrial ablation, which involves destruction of the endometrium while leaving the uterus in situ, is less invasive and leads to similar rates of patient satisfaction as hysterectomy [67]. Endometrial ablation is achieved by a variety of mechanisms, the initial methods involved hysteroscopic use of the neodymium-doped yttrium aluminium garnet laser; however, this method evolved into the use of a resection loop or roller ball to destroy the endometrium. Newer global systems have been developed that use bipolar or microwave energy, cryotherapy or hydrothermal techniques. Most of these newer techniques are easy to perform, take less time and do not require general anesthesia. Many providers are moving this procedure to the clinic and performing it in an office setting, which is acceptable to many patients [68]. Success with endometrial ablation is high, with 80–90% of patients reporting reduced bleeding and 25–50% achieving amenorrhea, depending on the technique used [69]. Most women (70–80%) report less menstrual pain; however, up to a third of patients may require reoperation within 5 years [67].

Hysterectomy achieves high levels of satisfaction but is associated with more perioperative morbidity and is a poor choice for women with medical conditions that significantly increase the risks of surgery [67]. Before embarking on hysterectomy, the risks of major surgery must be weighed against the risks of alternative management. In properly selected patients, hysterectomy may be the best choice.

Conclusion & future perspective

The underlying causes of AUB are poorly understood and this has considerably limited the development of medical treatment options. Further studies are needed in this area to investigate the underlying mechanisms so that the therapy can be more targeted to the cause. Diagnostic criteria for PCOS, particularly the clinical features (e.g., menstrual irregularity and acne) are considered ‘normal’ in adolescents and the multifollicular ovary of the normal adolescent also may be confused with the polycystic ovary of an adult women with PCOS. A diagnostic criteria for PCOS in adolescents is needed to correctly diagnose this disorder. In addition, futher studies are needed to assess the safety of OCP in adolescents.

Executive summary

Abnormal uterine bleeding

A confusing, inconsistent and overlapping array of terms has evolved to describe abnormal frequency, duration or volume of uterine bleeding. For this reason, the general term ‘abnormal uterine bleeding’ is often used instead of terms such as polymenorrhea, menorrhagia and oligomenorrhea.

Irregular menstrual bleeding can be either too frequent (a cycle of less than every 21 days) or infrequent (a cycle of more than every 36 days).

Menstrual irregularities in adolescents under 20 years old

Irregular uterine bleeding in adolescent girls may result from a wide spectrum of conditions. The most common cause is anovulation, which may be due to immaturity of hypothalamic–pituitary–ovarian axis or polycystic ovary syndrome (PCOS).

Menstrual irregularity associated with normal reproductive development is likely to resolve within the first 2 years following menarche, but persistent menstrual irregularity in adolescence may be an early presentation of PCOS.

All patients with dysfunctional uterine bleeding (DUB) are at risk for iron deficiency anemia and should be treated. The decision of whether to observe girls with DUB or to treat them with hormonal therapy depends upon patient and guardian considerations, as well as upon the severity and chronicity of the DUB.

All patients with PCOS should be managed with supportive therapy that encourages lifestyle changes, the maintenance of a healthy weight, exercise and diet. Oral contraceptive pills (OCPs) are the first-line endocrine treatment for women with the dermatologic or menstrual abnormalities of PCOS.

Menstrual irregularities in the reproductive age group: 20–40 years

Pregnancy should be considered as a possible cause in any sexually active reproductive-aged women. PCOS is the most common cause of irregular uterine bleeding in reproductive-aged women, affecting approximately 6% of this population. Endocrine disorders may be associated with hormonal changes that affect ovulation and cause irregular menstruation including thyroid dysfunction and hyperprolatinemia.

Menstrual irregularity should be treated in patients with PCOS, since chronic anovulation is associated with increased risk of developing endometrial hyperplasia and carcinoma. The major treatment options for menstrual irregularity include progestin or OCPs.

Menstrual irregularities in perimenopausal women over 40 years old

Menstrual bleeding irregularities are a hallmark of the menopausal transition but raise concerns about possible pregnancy, endometrial hyperplasia or gynecologic malignancy.

It is recommended that women with AUB, over the age of 45 years, should be investigated with hysteroscopy and endometrial biopsy.

Anovulatory irregular bleeding requires endometrial protection with a combined OCP, the levonorgestrel intrauterine system (LNG-IUS) or cyclic oral progestins. In cases in which persistent bleeding does not respond to medical or more conservative measures then hysterectomy could be considered, or conservative surgery, such as endometrical abation.

Footnotes

The authors have no relevant affliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Abnormal Uterine Bleeding: a Focus on Polycystic Ovary Syndrome

Abstract

Keywords

Normal menstrual cycle

Causes of menstrual irregularities in adolescents: less than 20 years old

Evaluation

History

Examination

Pelvic examination

Laboratory evaluation

Pelvic ultrasound

Management

Duration of therapy & follow-up

Causes of menstrual irregularities in the reproductive age group: 20–40 years

Evaluation

History

Examination

Laboratory evaluation

Pelvic ultrasound

Management

Menstrual irregularities in perimenopausal women: older than 40 years

Causes

Evaluation

Endometrial biopsy

Hysteroscopy

Management

Conclusion & future perspective

Footnotes

References