Ovarian cysts are a common cause of surgical procedures and hospitalizations among women worldwide. It has been reported that 5% to 10% of women will undergo surgery for an adnexal mass.1 Each year in the United States, more than 250,000 women are discharged from the hospital with a diagnosis of ovarian cyst.2 Because ovarian cysts are common, it is important for pharmacists to be knowledgeable about treatment options and the risk of malignancy.
Ovarian cysts may be classified as either functional ovarian cysts or ovarian cystic neoplasms (TABLE 1).3,4 The most common functional ovarian cysts are follicular cysts and corpus luteum cysts, which develop as a result of ovulation. It is believed that follicular cysts occur when an ovarian follicle fails to rupture and continues to grow.3 Corpus luteum cysts may develop when the corpus luteum fails to regress normally after ovulation.3 Because these cysts occur as a result of normal physiologic processes, they are termed functional cysts. Functional cysts are the most common type of ovarian cyst in premenopausal women.
Ovarian cystic neoplasms are derived from neoplastic growth. They may be categorized into three types based on their cells of origin: surface epithelial cell tumors, germ cell tumors, and sex cord-stromal tumors.5 The majority of these neoplasms are benign in women of reproductive age, but the risk of malignancy increases in postmenopausal women.4 As a group, epithelial tumors are the most common ovarian neoplasm; however, the single most common benign ovarian neoplasm is the benign cystic teratoma (also known as dermoid cyst), which is a germ cell tumor.3 Dermoid cysts are composed mainly of ectodermal tissue, which gives them their characteristic features of sebaceous glands, sweat glands, hair, and teeth.
Most ovarian cysts do not cause any noticeable symptoms and are found incidentally upon physical examination or ultrasound. Some women with functional ovarian cysts report a dull sensation or heaviness in the pelvis.6 Corpus luteum cysts are more likely than follicular cysts to cause pain, peritoneal irritation, and delayed menses.3 As an ovarian cyst enlarges, the patient may notice increased abdominal girth or pressure. Acute, severe lower-abdominal pain may indicate torsion or cyst rupture.
Risk Factors for Malignancy
The risk of ovarian malignancy increases dramatically with age. It is estimated that 13% of ovarian neoplasms in premenopausal women are malignant, compared with 45% in postmenopausal women.7 A thorough history may reveal other risk factors for ovarian cancer, such as a family history of ovarian or breast cancer, other hereditary cancer syndromes, infertility, and nulliparity.1 Carriers of the BRCA1 (breast cancer gene 1) mutation have a 60-fold increased risk of developing ovarian cancer by age 60 years, and carriers of the BRCA2 gene mutation have a 30-fold increased risk.8 Findings on ultrasound that are suspicious for malignancy include the presence of solid components, papillary projections, thick walls, thick septations, increased vascularity within the cyst, bilaterality, and ascites.1,9
Serum cancer antigen 125 (CA-125) has been studied as a screening tool for ovarian cancer. Elevated concentrations have been found in approximately 90% of women with advanced-stage epithelial ovarian cancer, but in only 50% of those with stage I ovarian cancer, when the chance of survival is greatest.1,7 In addition to the low sensitivity, specificity is low because CA-125 concentrations often are elevated in other benign conditions, such as liver disease, kidney disease, uterine fibroids, pelvic inflammatory disease, endometriosis, and pregnancy.1,7,8 Because these conditions occur more commonly in premenopausal women and ovarian cancer is more common in postmenopausal women, CA-125 measurement is of most benefit in the postmenopausal population.
It is difficult to distinguish a functional ovarian cyst from an ovarian neoplasm based on signs and symptoms alone. Transvaginal and transabdominal ultrasonography are useful for determining the location, size, and physical features of the cyst, as well as findings suggestive of malignancy. Measurement of CA-125 levels can be helpful for distinguishing between benign and malignant adnexal masses, especially in postmenopausal women. Although ovarian malignancy is less likely in women of reproductive age, any suspicion arising from patient history, signs and symptoms, imaging findings, or serologic testing should be further investigated.8 In many cases, a definitive diagnosis of cyst type and status as malignant or benign cannot be made without surgical excision and histologic examination.5
Management of Functional Ovarian Cysts
Ovarian follicular cysts often resolve spontaneously within one to two menstrual cycles. Transvaginal ultrasound may be repeated to check for disappearance of the cyst or a change in its size or characteristics. Resolution may occur following reabsorption of the cyst fluid or cyst rupture.6 The rupture of a follicular cyst may cause transient pelvic pain owing to the release of follicular fluid into the peritoneum; however, medical intervention usually is not necessary.4 Cysts that persist or change most likely will require surgical management.
Combined Hormonal Contraception: Suppression of ovulation should result in decreased cyst development, since functional cysts occur as a result of ovulation. Follicular growth and ovulation can be suppressed by inhibiting pituitary gonadotropins with combined oral contraceptives. Studies evaluating the effect of combined oral contraceptives on cyst occurrence have mixed results. High-dose oral combined hormonal contraceptives were shown in early epidemiologic studies to protect against cyst development.10 Advances in the understanding of hormonal contraception have led to the development of oral contraceptives with lower steroid doses; however, low-dose oral contraceptives do not suppress all follicular activity.11 Holt and colleagues conducted a case-control study of women aged 18 to 39 years with functional ovarian cysts to assess the effect of low-dose oral contraceptives on cyst occurrence.12 Compared with the 40% to 90% reduced risk of cyst occurrence seen in studies from the 1970s, this study found a modest 28% decrease in risk. The risk of cyst occurrence was slightly lower in women using 35 mcg ethinyl estradiol monophasic oral contraceptives versus women using monophasic or multiphasic oral contraceptives with less than 35 mcg of ethinyl estradiol.
Since combined oral contraceptives reduced the risk of cyst occurrence, it was theorized that they may also accelerate spontaneous regression of functional ovarian cysts or decrease cyst size. This hypothesis led to the use of combined oral contraceptives to treat pre-existing functional ovarian cysts. However, available evidence does not support this practice. A recent Cochrane review analyzed data from seven randomized, controlled trials of oral contraceptives (any type) used for the treatment of functional ovarian cysts in a total of 500 women.2 The primary outcome of the systematic review was cyst resolution. Two of the seven trials reported cysts associated with ovulation induction. The conclusion of the pooled analysis was that combined oral contraceptives did not hasten the resolution of functional ovarian cysts, compared with expectant management. The result was the same regardless of whether the cyst was related to ovulation induction or occurred spontaneously. Persistent cysts tended to not be physiologic. Based on the available evidence, the American College of Obstetricians and Gynecologists recommends that combined oral contraceptives not be used to treat existing functional ovarian cysts.11
Although combined oral contraceptives may be used in the management of functional ovarian cysts to prevent the development of new cysts, their use is not appropriate for all patients. Combined oral contraceptives should not be used in women with a history of thromboembolic disease, hypercoagulable states or other risk factors for thromboembolism, uncontrolled hypertension, migraines with aura, active liver disease, or cardiovascular or cerebrovascular disease.13 In addition, women who smoke--especially those over the age of 35 years--are at increased risk for myocardial infarction, so combined oral contraceptives are not recommended.13 Common adverse effects of combined oral contraceptives include breast tenderness, nausea, headaches, and bloating.14
Management of Benign Ovarian Neoplasms
Owing to their typically high fat content, dermoid cysts tend to be more buoyant in the pelvis than other types of neoplasms; therefore, they are more likely to result in ovarian torsion.4 Although the rate of malignancy is low, dermoid cysts are usually removed surgically owing to the increased risk of ovarian torsion and cyst rupture.
Other benign ovarian neoplasms are often surgically removed as well, owing to the potential for malignant transformation with increasing age.4 For women desiring future fertility, conservative surgical treatment with cystectomy rather than oophorectomy may be possible in some cases.
Simple Cysts in Postmenopausal Women
It is estimated that the incidence of adnexal masses in asymptomatic postmenopausal women is between 3% and 18%.7 The risk of malignancy is low if the cyst is unilocular and less than 10 cm in diameter.15 Many of these cysts resolve spontaneously, but some will persist or become complex. Large, complex cysts in postmenopausal women have an estimated frequency of malignancy of 6% to 39%.1 Based on these findings, postmenopausal women with a small (<5 cm), simple (unilocular) ovarian cyst that is not suspicious for malignancy and who have a normal CA-125 level and no family history may choose expectant management with serial ultrasounds and CA-125 measurements.6,7 However, if the cyst is persistent, enlarges, or shows findings suggestive of malignancy on ultrasound, or if the CA-125 level increases, the cyst should be surgically removed and examined for malignancy.
The type of surgical approach used for ovarian cyst removal depends upon several factors. The laparoscopic approach typically is used for benign ovarian cysts that are less than 10 cm in diameter.16 A recent Cochrane review evaluated the benefits and risks of laparoscopy versus laparotomy in 12 randomized trials involving 769 patients with benign ovarian tumors.16 Patients who underwent laparoscopy had a decreased risk of adverse events from surgery, experienced less pain, and spent fewer days in the hospital than patients who underwent traditional laparotomy. No difference was found in rates of fever, postoperative infections, or tumor recurrence between the two procedures.
For patients with a mass suspected of malignancy based on ultrasound findings, CA-125 levels, and clinical assessment, laparotomy is generally recommended.8 Laparotomy often is preferred in these patients owing to the risk of cyst rupture and tumor spillage with laparoscopy.
Referral to Gynecologic Oncologist
It is recommended that premenopausal women with a CA-125 level greater than 200 U/mL, ascites, evidence of abdominal or distant metastasis, or family history of breast or ovarian cancer in a first-degree relative be referred to a gynecologic oncologist for surgical evaluation. Postmenopausal women should be referred if they have a CA-125 level greater than 35 U/mL, ascites, nodular or fixed pelvic mass, evidence of abdominal or distant metastasis, or family history of breast or ovarian cancer in a first-degree relative.8 Should a malignancy be found, studies have shown that survival is improved when the malignancy is properly staged and aggressively debulked by a gynecologic oncologist.9,17,18
Ovarian cysts are a common occurrence in women of all ages. Pharmacists may be asked about the condition by their patients, especially if the patient is using hormonal contraceptives or is undergoing ovulation induction. Functional ovarian cysts are physiologic and usually resolve spontaneously within a couple of menstrual cycles. Combined oral contraceptives may be used to prevent the occurrence of these cysts; however, they do not accelerate cyst resolution. Ovarian neoplasms often are benign in women of reproductive age. The risk of an ovarian mass being malignant increases with age. Measurement of CA-125 may be helpful in distinguishing between benign and malignant ovarian masses, especially in postmenopausal women. While laparoscopy is commonly used to remove benign cysts, laparotomy is often preferred for removal of masses that may be malignant. In women with certain findings suggestive of malignancy, survival is increased when prompt referral to a gynecologic oncologist is made.
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