The burden of uterine fibroids: an overview

Uterine leiomyomas, or fibroids, are smooth muscle tumors that originate from the myometrium, or outer muscular layer, of the uterus [1]. The occurrence of fibroid disease varies with age and can be detected in 80% of women by the time they reach 50 years of age. Fibroids constitute the primary reason for hysterectomies, representing 40% of all hysterectomies carried out each year in the United States. Although benign, these tumors clinically manifest in 25–50% of women by the age of 50 and are commonly associated with heavy menstrual bleeding [2,3]. Other symptoms include anemia, pelvic pressure, low back pain, infertility, and preterm labor [2]. Accordingly, the societal and financial cost of these tumors is estimated to range from $5 to $34 billion [4].

Epidemiology and etiology

Depending on location, fibroids are classified as subserosal, intramural, submucosal, or pedunculated [2]. In general, submucosal fibroids tend to be more commonly associated with menorrhagia, fertility issues, and an increased risk of preterm birth or miscarriage.

Age is a significant risk factor for uterine fibroids, particularly among premenopausal women and those aged 40 or older [3]. This could be a result of previously asymptomatic fibroids becoming more noticeable with age and exposure to steroid hormones. These tumors are not typically found in prepubertal girls, with only sporadic cases reported in adolescents. Following menopause, uterine fibroids tend to be smaller and asymptomatic [5].

Fibroids occur disproportionally in women of African American descent, with a higher incidence, larger tumors, severe symptoms, and an earlier age of incidence. Black women are 2.4 times more likely to undergo hysterectomy and have a 6.8-fold higher myomectomy rate for fibroid treatment compared to White women. Compared to White women, Black women are diagnosed with fibroids at a much younger age, report increased pain due to fibroids, have increased uterine weight, and multiple fibroids, and are at increased risk of anemia due to the size and location of fibroids. The earlier onset of the disease is also more likely to impact pregnancy and fertility in Black women. Apart from severe symptoms and impairment, Black women also face disparities based on socioeconomic status and access to health care and insurance. Among women with access to equal care, there is a race-dependent outcome on treatment, suggesting that uterine fibroids in Black women may be biologically different [6,7].

Uterine fibroids are dependent on sex steroid hormones. Following puberty, endogenous estrogen levels influence uterine growth and development and regress following menopause [2]. Fibroids also have increased expression of the progesterone receptor (PR) and estrogen receptor (ER), making them hypersensitive to steroid hormones, unlike normal myometrium. The more common occurrence of fibroids in Black women has been attributed to higher estradiol levels compared to White women [8].

In addition to age, race, and steroid hormones, other factors known to influence fibroids include obesity, parity, family history, exposure to endocrine-disrupting chemicals, and vitamin D deficiency [1,2,9].

Diagnosis

Ultrasonography using transvaginal and transabdominal techniques remains the most cost-effective and frequently used methods to detect uterine fibroids. Fibroids are typically round, well-defined masses with a whorled appearance. However, the presence of calcification and necrosis can complicate diagnosis. Conditions such as endometriosis, leiomyosarcoma, uterine carcinosarcoma, or endometrial cancer present similar symptoms to fibroid. Accurate prognosis is therefore important to ensure the management and treatment of diseases and prevent misdiagnosis. Consequently, when in doubt, further evaluation is performed using MRI [10].

While cost-prohibitive, the increased sensitivity and specificity of MRI remain the most accurate method to detect and differentiate fibroids from focal adenomyosis. It can even identify fibroids as small as 5 mm in diameter, including those in uncommon locations like the cervix [11].

Management

There remains a lack of long-term therapeutic options, and medical treatments are only used for short-term therapy. Many women with symptomatic fibroids have high menstrual bleeding and may be anemic. Combined oral contraceptives (COC) are widely used to reduce blood loss and correct anemia. While short-term treatment with COC improves heavy menstrual bleeding, it has a reduced effect on uterine fibroid size and volume [12].

GnRH analogs (GnRHa) are frequently used preoperatively to induce fibroid tumor shrinkage. GnRHa treatment results in increased secretion of follicle-stimulating hormone and luteinizing hormone, ultimately leading to inhibition of the pituitary-gonadal axis. The use of GnRHa helps decrease operative times, intraoperative bleeding, and the duration of hospital stays. However, the cost of treatment, menopausal symptoms, and possible bone demineralization with prolonged treatment remain major drawbacks of GnRHa treatment. In some cases, smaller fibroids overlooked during surgery may recur following cessation of GnRHa therapy [13].

Selective estrogen receptor modulators (SERMs) are non-steroidal estrogen receptor ligands that are thought to act by modulating estrogen receptors, resulting in blockage of estrogen activity. However, negative side effects and limited effectiveness on fibroid size outweigh marginal benefits, and its use is not generally recommended [14].

Selective progesterone receptor modulators (SPRMs) target progesterone receptors and have emerged as promising therapies for the management of uterine fibroids. These agents have been shown to reduce uterine bleeding, increase fibroid volume, and improve overall quality of life. Historically, mifepristone was the first PR antagonist and was clinically used for over 25 years. More recently, ulipristal acetate (UPA) has completed Phase III clinical trials. UPA was well tolerated, with fibroid patients exhibiting controlled uterine bleeding and being significantly less likely to cause hot flushes [15].

The standard treatment for fibroids remains surgical, either in the form of myomectomy, where the patient would like to retain the uterus for pregnancy or complete removal of the uterus through hysterectomy. Small fibroids (<2 cm) are routinely removed by a standard minimally invasive hysteroscopic myomectomy. The most common perioperative complications associated with hysteroscopic myomectomy include hemorrhage and uterine perforation. However, surgical removal of submucous and intramural fibroid increased pregnancy rate and decreased the rate of miscarriage. Laparoscopic myomectomy remains a common approach for addressing symptomatic subserosal fibroids and can also be considered for intramural fibroids, depending on their location. In cases of large, numerous, or deeply embedded uterine fibroids, an abdominal myomectomy may become necessary [16].

The final and definitive approach to treating uterine fibroids remains hysterectomy. Women experiencing symptoms who do not wish to preserve fertility and do not respond to conservative treatments may find relief through hysterectomy. Surgical approaches for hysterectomy include vaginal, abdominal, and laparoscopic. Laparoscopic techniques offer several advantages, including decreased postoperative pain and shorter hospital stays [17]. While benign, uterine fibroids can significantly impact the well-being of women, both during their reproductive years and sometimes even after menopause, Consequently, there is substantial interest in identifying approaches to targeted therapy, which will remove hysterectomy as the only fail-safe treatment for fibroids.