Uterine Abnormalities



Uterine Abnormalities


Lubna Chohan



INTRODUCTION



History

As time has progressed, women’s health issues have become increasingly important. Much of this can be contributed to the increased life expectancy of women and their added contribution to the work force. Life expectancy was 50 years of age for females in 1900.1 In the United States in 2006, this increased to 80.2 years of age for females.2 Women with excessive menstrual bleeding suffer both economic and psychosocial costs including discomfort and diminished quality of life. Work and school status can suffer from stained clothes, lost time, and extra cost of menstrual products. A survey of 2805 American women showed those that had increased menstrual flow during the prior year were more likely to be unemployed than women with a normal flow. It is estimated that the cost of this work loss is $1692 annually per woman.3



Definitions

Most definitions of normal menstruation include a cycle length of 21 to 35 days, duration of 7 days or less, and blood loss of less than 80 mL. These values come from a Swedish study done in 1966. About 500 women (ranging from adolescence through their 50s) were studied. Blood loss was estimated after collecting menstrual pads and tampons and using the alkaline hematin method. Median blood loss was 30 mL per month with 10% of women losing greater than 90 mL per month. Greater blood loss was found in perimenopausal women.3

Abnormal uterine bleeding is somewhat subjective as practitioners base their assessment on a patient’s history. Even if a woman’s menstrual blood loss is greater than 80 mL, many of them consider this to be normal. These patients oftentimes seek treatment once their quality of life is affected, not because of bleeding symptoms. For those with a blood loss of less than 80 mL per month, 25% of women will be anemic (hemoglobin less than 12 g/dL). For those with a blood loss of greater than 80 mL per month, 67% are anemic.3 Table 2.1 includes other standard definitions regarding abnormal uterine bleeding. To note, heavy menstrual bleeding is a newer term for menorrhagia.4


Endocrinology and Pathology

The menstrual cycle is endometrial breakdown and remodeling in a cyclical fashion. This tissue has well-defined episodes of proliferation, differentiation, and breakdown. Menstruation occurs in response to the withdrawal of ovarian steroids. This causes the uterine functional layer (upper two-thirds of endometrium) to shed and regenerate on a regular basis. The functional layer is then replenished after menstruation by exposure to estradiol then progesterone.5

After menstruation, the vascular compartment of the endometrium comprising the spiral arteries and arterioles needs to be reconstructed. New endothelial cells are formed and growth begins of capillaries and smooth muscle cells to form larger vessels. The remodeling of the endometrial vasculature is a multifactorial and complex process.5

Prostaglandins have a role in endometrial pathology and subsequently abnormal uterine bleeding. Arachidonic acid is broken down into prostaglandins by cyclooxygenase (COX) and lipoxygenase (LOX). At the end of the menstrual cycle with progesterone withdrawal and shedding of the endometrial functional layer, there is an increase in COX-2 expression that lasts through the proliferative phase. Data suggests that prostaglandins produced by COX enzymes in the endometrium directly control endometrial angiogenesis.5

Treatment with COX enzyme inhibitors have been shown to reduce menstrual blood loss and points toward disturbances of prostaglandin pathways in menorrhagia.5 With ovulatory abnormal uterine bleeding in the absence of underlying pathology (i.e., leiomyomas), there is no difference in circulating steroid hormones or endometrial histology when compared to women with normal menses. It has been shown that disturbances of arachidonic acid metabolism and angiogenic processes and elevated levels of prostaglandin E2 (PGE2) in endometrium are found in women with menorrhagia. A dual mode of action has been shown for COX inhibitors used in the treatment of menorrhagia: inhibition of prostaglandin synthesis and inhibition of PGE2 binding to its receptor.5

Women with heavy menses have endometrial endothelial cells that proliferate more. Also, their spiral arterioles have less vascular smooth muscle cells. This then
prevents proper vasoconstriction of these vessels and subsequent increased menstrual blood loss.5








TABLE 2.1 Definitions

























Oligomenorrhea: Intervals between bleeding episodes vary from 35 days to 6 months


Amenorrhea: No menses for at least 6 months

Primary amenorrhea: Absence of menstruation in a 16-year-old with developed secondary sexual characteristics or in a 14-year-old with absent secondary sexual characteristics

Secondary amenorrhea: Absence of menses for 6 months in females with previously irregular menstrual pattern


Menorrhagia: Prolonged (more than 7 days) or excessive (greater than 80 mL) uterine bleeding occurring at regular intervals; also called heavy menstrual bleeding


Metrorrhagia: Uterine bleeding occurring at irregular but frequent intervals, the amount being variable


Intermenstrual bleeding: Bleeding of variable amounts occurring between regular menstrual periods


Polymenorrhea: Uterine bleeding occurring at regular intervals of less than 21 days


Dysfunctional uterine bleeding (DUB): Excessive uterine bleeding with no demonstrable organic cause (genital or extragenital). It is most frequent due to abnormalities of endocrine origin, particularly anovulation.


Data from Nelson AL. LNG-IUS: First-line therapy for idiopathic heavy menstrual bleeding. The Female Patient. 2010;35:39-43; Deligeoroglou E, Athanasopoulos N, Tsimaris P, et al. Evaluation and management of adolescent amenorrhea. Ann N Y Acad Sci. 2010;1205:23-32; Katz VL, Lentz GM, Lobo RA, et al. Abnormal uterine bleeding. In: Katz VL, Lentz GM, Lobo RA, et al, eds. Comprehensive Gynecology. 5th ed. St Louis, MO: Mosby Elsevier; 2007:915.



ETIOLOGY


Anovulation

In adolescents, abnormal uterine bleeding is commonly related to anovulation from an immature hypothalamic-pituitary axis. This results in months to years of unpredictable ovulation after menarche.6 For these first few years, normal cyclic progesterone production lags behind the normal development of GnRH and estrogen. In the first year after menarche, 85% of cycles are anovulatory. Four years after menarche, only 56% of cycles are ovulatory.6 If menarche occurs earlier, there is a faster normalization of ovulation when compared to girls with a delayed menarche.6

Another source of anovulatory menstrual bleeding is polycystic ovarian syndrome (PCOS). This is thought to occur in up to 10% of adolescents6 and 6 to 8% of reproductive-aged women.7 Clinical features of PCOS include polycystic ovaries, anovulation causing menstrual irregularities, and hyperandrogenism causing hair growth and acne. It is also related to insulin resistance, obesity, and infertility. Reproductive and metabolic abnormalities of PCOS include overproduction of ovarian androgens, increased pituitary luteinizing hormone (LH) secretion, incomplete maturation of ovarian follicle development, and insulin resistance with compensatory hyperinsulinemia.7 During times of chronic anovulation, there is prolonged unopposed estrogen which can lead to excessive endometrial proliferation. When the endometrial thickness grows beyond its available blood supply, the superficial layers slough and breakthrough bleeding occurs.7

Other causes of anovulation secondary to disturbances in the hypothalamic-pituitary-ovarian axis include stress, excessive exercise, eating disorders, thyroid disease, and menopausal transition.8


Hematologic Disorder

Bleeding disorders can cause abnormal uterine bleeding and should be evaluated, especially in the adolescent. It is estimated that bleeding disorders have a 2% community prevalence rate.9 In women with heavy menstrual bleeding, bleeding disorders are reported at 10 to 20%9 and even higher in adolescents (7 to 48%).6 Other bleeding symptoms that are predictive of these diseases include bleeding after tooth extraction, epistaxis, prolonged bleeding after wounds, postoperative bleeding, postpartum hemorrhage, and family history of bleeding disorders. Platelet abnormalities (platelet function defects and thrombocytopenia) and von Willebrand disease (VWD) should be considered. The most common inherited bleeding disorder is VWD with a 1% incidence, but only 125 per million have a clinically significant bleeding disorder.9


Uterine Pathology


Leiomyomas

Leiomyomas (or myomas or fibroids) occur in 20 to 50% of women, making them the most common solid pelvic tumors in women.10,11 Some studies show a prevalence of up to 80% in African American women and 70% in Caucasian women by 50 years of age.11 This is the most common diagnosis for hysterectomy in the United States.10 Myomas originate from smooth muscle cells of the uterus and are benign. They range in size, number, and location, including intramural (within the myometrium), subserosal (externally extending to the serosa), submucosal (internally impinging on the uterine cavity), and pedunculated. They are estrogen dependent and decrease in size during menopause and other hypoestrogenic conditions. There is a higher concentration of estrogen receptors in myomas than in adjacent myometrium. Fibroids bind 20% more estradiol per milligram of protein than myometrium.10

About 30% of fibroids become symptomatic (abnormal uterine bleeding and pelvic pressure).11 Heavy menstrual bleeding occurs secondary to an obstructive effect of myomas on uterine vasculature and subsequent congestion in proximal myometrium/endometrium causing excessive bleeding during cyclic endometrial sloughing. Histologically, endometritis is often seen in tissue
overlying submucosal fibroids, which may also contribute to abnormal uterine bleeding.10

The transition of myomas to malignant tumors is extremely rare. It is thought that leiomyosarcomas may be unrelated to benign fibroids. In a study of about 1300 women with symptomatic fibroids undergoing myomectomy or hysterectomy, uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma, and mixed mesodermal tumor) was seen in 0.2%.10 A more realistic percentage is likely much lower than 0.2% if you consider all women with fibroids; only a small percentage are symptomatic and require myomectomy or hysterectomy. As stated previously, fibroids decrease in size during menopause. If a rapid growth of myomas occurs in a menopausal patient, the concern for malignancy should arise.


Endometrial Hyperplasia and Cancer

As age increases, so does the risk of endometrial carcinoma. At the time of diagnosis, the median age is 61 years, with 75 to 80% of women being postmenopausal.12 The prevalence of carcinoma in women age 40 years or younger varies from 2.9 to 14.4%.12 In regards to endometrial hyperplasia, there is a 2 to 7% prevalence in premenopausal women.12 The progression rate to endometrial cancer is 1% for simple hyperplasia (mean duration 10 years), 2 to 4% for complex hyperplasia (mean duration 10 years), 23% for atypical hyperplasia (mean duration 4 years), and 29% for complex atypical hyperplasia (mean duration 4 years).12 Ninety-five percent of women with endometrial cancer present with postmenopausal bleeding as their only complaint. Of all women who have postmenopausal bleeding, 3 to 10% have endometrial cancer.13

Recommendations for endometrial sampling range widely from all women older than 35 years of age with abnormal uterine bleeding or those who do not respond to initial management in the United States to women older than 45 years of age with cyclical heavy bleeding, greater than 90 kg, or have other risk factors for carcinoma in New Zealand.12 In one of the largest series studying the appropriate age for endometrial sampling, findings included atypical hyperplasia and carcinoma being significantly higher in women 45 to 50 years than in younger age women. They also found importance in distinguishing anovulatory abnormal uterine bleeding because this is more likely to lead to hyperplasia versus ovulatory bleeding. Other risk factors for hyperplasia and cancer included nulliparity; obesity (greater than 90 kg); polycystic ovaries with anovulation; family history of endometrial or colon cancer; tamoxifen treatment; and a triad of obesity, diabetes, and hypertension.12


Endometrial Polyps

Endometrial polyps are being diagnosed more frequently secondary to the improved quality of transvaginal ultrasound, saline-infusion ultrasounds, and hysteroscopy.14 It is thought that estrogen stimulation of the endometrium plays a role in the creation of these polyps. Women who are symptomatic can have abnormal bleeding: intermenstrual bleeding, heavy menstrual bleeding, spotting, discharge, or postmenopausal bleeding. Asymptomatic premenopausal patients may have polyps that resolve spontaneously. Also, polyps less than 1 cm may resolve.14

In a systematic review and meta-analysis including 17 studies and over 10,000 patients, the association of menopause, abnormal bleeding, polyp size, and malignancy risk in regards to endometrial polyps were studied.14 Endometrial neoplasia was found in 5.4% of postmenopausal patients compared to 1.7% of premenopausal patients. In regards to abnormal uterine bleeding, neoplasia was seen in 4.2% of women with symptomatic bleeding versus 2.2% of asymptomatic women. This review concluded that there is an increased risk of endometrial neoplasia in women with endometrial polyps who have symptomatic bleeding or are postmenopausal. Overall, an association with polyp size was not noted.14

In a smaller retrospective multicenter study, the malignant potential of endometrial polyps was studied in approximately 2000 postmenopausal women.15 The prevalence of endometrial carcinoma was 0.1% for asymptomatic menopausal patients. This was 10 times lower than for symptomatic (any bleeding or spotting in the prior 6 months) patients. For asymptomatic women, the only variable significantly associated with cancer or hyperplasia was polyp diameter (larger than 18 mm).15 Both of these studies conclude that there is a higher rate of cancer in women with symptomatic endometrial polyps.


Endocrine Disorder

Major endocrine causes of abnormal uterine bleeding and amenorrhea include polycystic ovarian syndrome, thyroid disease, and hyperprolactinemia. When prolactin is elevated, hypothalamic GnRH secretion is suppressed. This in turn can affect circulating estrogen levels and menstrual cycles. Causes of hyperprolactinemia include stress, thyroid disease, medications, and pituitary tumors. If prolactin is mildly elevated, this may be due to stress and the level should be remeasured. With hypothyroidism, the stimulating effect of thyrotropin-releasing hormone (TRH) in the pituitary gland can cause elevated prolactin. Prolactin is inhibited by dopamine. With antipsychotic drugs, these block dopamine receptors and subsequently increase prolactin. Also, with pituitary tumors, these place pressure on the pituitary stalk, obstruct dopamine flow, and cause prolactinemia. These patients are often treated with dopamine receptor agonists (i.e., bromocriptine or cabergoline).16
Other endocrine disorders were discussed previously (i.e., PCOS).








TABLE 2.2 Etiology of Abnormal Genital Bleeding























































































































Cancer


Infection


Benign

Pregnancy

Uterus


  • Polyps



  • Endometrial hyperplasia



  • Adenomyosis



  • Leiomyomas

Cervix


  • Polyps



  • Ectropion



  • Endometriosis

Vulva


  • Skin tags



  • Sebaceous cyst



  • Condylomata



  • Angiokeratoma

Vagina


  • Gartner’s duct cyst



  • Polyps



  • Adenosis


Trauma

Abuse

Foreign body

Pelvic trauma/straddle injury


Drugs

Contraception

Hormone replacement therapy

Anticoagulant

Tamoxifen

Corticosteroids

Chemotherapy

Dilantin

Antipsychotics


Systemic disease

Coagulation disorder


  • von Willebrand disease



  • Thrombocytopenia or platelet dysfunction



  • Acute leukemia



  • Factor deficiencies



  • Advanced liver disease

Thyroid disease

Hyperprolactinemia

Polycystic ovarian syndrome

Chronic liver disease

Cushing syndrome

Hormone secreting adrenal and ovarian tumors

Renal disease

Emotional and physical stress

Smoking

Excessive exercise

Vulvar disease


  • Crohn disease



  • Behçet syndrome



  • Pemphigoid



  • Pemphigus



  • Erosive lichen planus



  • Lymphoma


Data from Goodman A. Initial approach to the premenopausal woman with abnormal uterine bleeding. UpToDate Web site. http://www.uptodate.com/contents/initial-approach-to-the-premenopausal-woman-with-abnormal-uterine-bleeding. Accessed December 2, 2013; DeSilva NK. Differential diagnosis and approach to the adolescent with abnormal uterine bleeding. UpToDate Web site. http://www.uptodate.com/contents/differential-diagnosis-and-approach-to-the-adolescent-with-abnormal-uterine-bleeding. Accessed December 2, 2013; Goodman A. Overview of causes of genital tract bleeding in women. UpToDate Web site. http://www.uptodate.com/contents/overview-of-causes-of-genital-tract-bleeding-in-women. Accessed December 2, 2013.


In regards to causes of abnormal genital tract bleeding and causes by age groups, a more comprehensive list is included in Tables 2.2 and 2.3.


EVALUATION


Laboratory

A pregnancy test should be performed on patients with abnormal uterine bleeding. Other labs include complete blood cell count, thyroid-stimulating hormone, prolactin, LH, follicle-stimulating hormone, and liver and renal function tests.

When concerned about bleeding disorders, check a complete blood cell count, prothrombin time, activated partial thromboplastin time, factor VIII, and von Willebrand Factor (VWF) ristocetin cofactor and antigen. It is advised to screen for VWD before initiating hormonal therapy because exogenous estrogen can elevate VWF into a normal range, thus giving a false-negative result.6 This is why pregnant women normalize their factor VIII, von Willebrand antigen level, and ristocetin cofactor activity and usually do not bleed during the pregnancy. However, they can start bleeding within a few days postpartum as these levels decrease.9








TABLE 2.3 Etiology of Abnormal Genital Bleeding by Age Group





























Neonates




  • Estrogen withdrawal


Premenarchal




  • Foreign body



  • Trauma/abuse



  • Infection



  • Urethral prolapse



  • Sarcoma botryoides



  • Ovarian tumor



  • Precocious puberty


Early postmenarche




  • Anovulation (hypothalamic immaturity)



  • Bleeding diathesis



  • Stress



  • Pregnancy



  • Infection


Reproductive years




  • Anovulation



  • Pregnancy



  • Cancer



  • Polyps



  • Leiomyomas



  • Adenomyosis



  • Infection



  • Endocrine dysfunction (polycystic ovarian syndrome, thyroid, pituitary)



  • Bleeding diathesis



  • Medications


Perimenopausal




  • Anovulation



  • Polyps



  • Leiomyomas



  • Adenomyosis



  • Cancer


Menopause




  • Atrophy



  • Cancer



  • Hormone replacement therapy


Data from Wilkinson JP, Kadir RA. Management of abnormal uterine bleeding in adolescents. J Pediatr Adolesc Gynecol. 2010;23(6)(suppl):S22-S30; Goodman A. Initial approach to the premenopausal woman with abnormal uterine bleeding. UpToDate Web site. http://www.uptodate.com/contents/initial-approach-to-the-premenopausal-woman-with-abnormal-uterine-bleeding. Accessed December 2, 2013; DeSilva NK. Differential diagnosis and approach to the adolescent with abnormal uterine bleeding. UpToDate Web site. http://www.uptodate.com/contents/differential-diagnosis-and-approach-to-the-adolescent-with-abnormal-uterine-bleeding. Accessed December 2, 2013.


If clinical hyperandrogenism is present, also check testosterone and dehydroepiandrosterone sulfate (DHEA-S). If DHEA-S is elevated, then adrenal gland function should be investigated with 17OH-progesterone. If DHEA-S is greater than 700 mg/dL, consider late-onset type congenital adrenal hyperplasia as a diagnosis.16 A list of laboratory tests to consider in the workup of abnormal uterine bleeding is included in Table 2.4.


Endometrial Sampling

There is not a worldwide consensus on when to perform an endometrial sampling. Some countries advocate endometrial sampling after 45 years or with risk factors for endometrial hyperplasia/carcinoma.12 In the United States, with the American College of Obstetricians and Gynecologists (ACOG) support, the recommendation is
for endometrial sampling in women older than 35 years of age with abnormal uterine bleeding or those who do not respond to initial management.12 In 2009, an ACOG Committee Opinion stated that postmenopausal patients with an endometrial echo of 4 mm or less (by transvaginal ultrasound) had a malignancy risk of 1 in 917 and did not require an endometrial biopsy. There are limitations of ultrasound and will be discussed in the following section.17

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Jun 25, 2016 | Posted by in GYNECOLOGY | Comments Off on Uterine Abnormalities

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