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Uterine fibroids are a common cause of menorrhagia and anemia, and the incidence is extremely high, about 70% to 80% of women will develop uterine fibroids in their lifetime, of which 50% show symptoms. Currently, hysterectomy is the most commonly used treatment and is considered a radical cure for fibroids, but hysterectomy carries not only perioperative risks, but also an increased long-term risk of cardiovascular disease, anxiety, depression, and death. In contrast, treatment options such as uterine artery embolization, local ablation, and oral GnRH antagonists are safer but not fully used.

Case summary

A 33-year-old black woman who had never been pregnant presented to her primary practitioner with heavy menstruation and abdominal gas. She suffers from iron deficiency anemia. Tests came back negative for thalassemia and sickle cell anemia. The patient had no blood in the stool and no family history of colon cancer or inflammatory bowel disease. She reported regular menstruation, once a month, each period of 8 days, and long-term unchanged. On the three most prolific days of each menstrual cycle, she needs to use 8 to 9 tampons a day, and occasionally has menstrual bleeding. She is studying for her doctorate and plans to get pregnant within two years. Ultrasound showed an enlarged uterus with multiple myomas and normal ovaries. How will you treat the patient?

The incidence of disease associated with uterine fibroids is compounded by the low detection rate of the disease and the fact that its symptoms are attributed to other conditions, such as digestive disorders or disorders of the blood system. The shame associated with discussing menstruation causes many people with long periods or heavy periods to not know that their condition is abnormal. People with symptoms are often not diagnosed in time. A third of patients take five years to be diagnosed, and some take more than eight years. Delayed diagnosis can adversely affect fertility, quality of life, and financial well-being, and in a qualitative study, 95 percent of patients with symptomatic fibroids reported psychological after-effects, including depression, worry, anger, and body image distress. The stigma and shame associated with menstruation hinder discussion, research, advocacy, and innovation in this area. Among patients diagnosed with fibroids by ultrasound, 50% to 72% were not previously aware that they had fibroids, suggesting that ultrasound may be more widely used in the evaluation of this common disease.

The incidence of uterine fibroids increases with age until menopause and is higher in blacks than in whites. Compared with people other than black people, black people develop uterine fibroids at a younger age, have a higher cumulative risk of developing symptoms, and have a higher overall disease burden. Compared with Caucasians, black people are sicker and more likely to undergo hysterectomy and myomectomy. In addition, blacks were more likely than whites to opt for non-invasive treatment and to avoid surgical referrals in order to avoid the possibility of undergoing hysterectomy.

Uterine fibroids can be diagnosed directly with a pelvic ultrasound, but determining who to screen for is not easy, and currently screening is usually done after a patient’s fibroids are large or symptoms appear. Symptoms associated with uterine fibroids may overlap with symptoms of ovulation disorders, adenomyopathy, secondary dysmenorrhea, and digestive disorders.

Because both sarcomas and fibroids present as myometric masses and are often accompanied by abnormal uterine bleeding, there is concern that uterine sarcomas may be missed despite their relative rarity (1 in 770 to 10,000 visits due to abnormal uterine bleeding). Concerns about undiagnosed leiomyosarcoma have led to an increase in the rate of hysterectomy and a decrease in the use of minimally invasive procedures, putting patients at an unnecessary risk of complications due to the poor prognosis of uterine sarcomas that have spread outside the uterus.

Diagnosis and evaluation

Of the various imaging methods used to diagnose uterine fibroids, pelvic ultrasound is the most cost-effective method because it provides information on the volume, location, and number of uterine fibroids and can exclude adnexal masses. An outpatient pelvic ultrasound may also be used to evaluate abnormal uterine bleeding, a palpable pelvic mass during the examination, and symptoms associated with uterine enlargement, including pelvic pressure and abdominal gas. If the uterine volume exceeds 375 mL or the number of fibroids exceeds 4 (which is common), the resolution of the ultrasound is limited. Magnetic resonance imaging is very useful when uterine sarcoma is suspected and when planning an alternative to hysterectomy, in which case accurate information about uterine volume, imaging features, and location is important for treatment outcomes (Figure 1). If submucosal fibroids or other endometrial lesions are suspected, saline perfusion ultrasound or hysteroscopy may be helpful. Computed tomography is not useful for diagnosing uterine fibroids because of its poor clarity and visualization of the tissue plane.

In 2011, the International Federation of Obstetrics and Gynecology published a classification system for uterine fibroids with the aim of better describing the location of fibroids in relation to the uterine cavity and serous membrane surface, rather than the old terms submucosal, intramural, and subserous membranes, thus allowing for clearer communication and treatment planning (supplementary Appendix table S3, available with the full text of this article at NEJM.org). The classification system is type 0 to 8, with a smaller number indicating that the fibroid is closer to the endometrium. Mixed uterine fibroids are represented by two numbers separated by hyphens. The first number indicates the relationship between the fibroid and the endometrium, and the second number indicates the relationship between the fibroid and the serous membrane. This uterine fibroid classification system helps clinicians target further diagnosis and treatment, and improves communication.

Treatment

In most regimens for the treatment of myoma-associated menorrhagia, controlling menorrhagia with contraceptive hormones is the first step. Nonsteroidal anti-inflammatory drugs and tranatemocyclic acid used during menstruation can also be used to reduce menorrhagia, but there is more evidence on the efficacy of these drugs for idiopathic menorrhagia, and clinical trials on the disease usually exclude patients with giant or submucosal fibroids. Long-acting gonadotropin-releasing hormone (GnRH) agonists have been approved for the preoperative short-term treatment of uterine fibroids, which can cause amenorrhea in nearly 90% of patients and reduce uterine volume by 30% to 60%. However, these drugs are associated with a higher incidence of hypogonadal symptoms, including bone loss and hot flashes. They also cause “steroidal flares” in most patients, in which stored gonadotropins in the body are released and cause heavy periods later when estrogen levels drop rapidly.

The use of oral GnRH antagonist combination therapy for the treatment of uterine fibroids is a major advance. Drugs approved in the United States combine oral GnRH antagonists (elagolix or relugolix) in a compound tablet or capsule with estradiol and progesterone, which rapidly inhibit ovarian steroid production (and do not cause steroid triggering), and estradiol and progesterone doses that make systemic levels comparable to early follicular levels. One drug already approved in the European Union (linzagolix) has two doses: a dose that partially inhibits hypothalamic function and a dose that completely inhibits hypothalamic function, which is similar to the approved doses for elagolix and relugolix. Each drug is available in preparation with or without estrogen and progesterone. For patients who do not wish to use exogenous gonadal steroids, a low-dose linzagolix formulation without the addition of gonadal steroids (estrogen and progesterone) can achieve the same effect as a high-dose combination formulation containing exogenous hormones. Combination therapy or therapy that partially inhibits hypothalamic function can relieve symptoms with effects comparable to full-dose GnRH antagonist monotherapy, but with fewer side effects. One advantage of high-dose monotherapy is that it can reduce the size of the uterus more effectively, which is similar to the effect of GnRH agonists, but with more hypogonadal symptoms.

Clinical trial data show that the oral GnRH antagonist combination is effective in reducing menorrhagia (50% to 75% reduction), pain (40% to 50% reduction), and symptoms associated with uterine enlargement, while slightly reducing uterine volume (approximately 10% reduction in uterine volume) with fewer side effects (<20% of participants experienced hot flashes, headache, and nausea). The efficacy of oral GnRH antagonist combination therapy was independent of the extent of myomatosis (size, number, or location of the fibroids), the complicity of adenomyosis, or other factors limiting surgical therapy. The oral GnRH antagonist combination is currently approved for 24 months in the United States and for indefinite use in the European Union. However, these drugs have not been shown to have a contraceptive effect, which limits long-term use for many people. Clinical trials evaluating the contraceptive effects of the relugolix combination therapy are ongoing (registration number NCT04756037 at ClinicalTrials.gov).

In many countries, selective progesterone receptor modulators are a drug regimen. However, concerns about rare but serious liver toxicity have limited the acceptance and availability of such drugs. No selective progesterone receptor modulators have been approved in the United States for the treatment of uterine fibroids.

Hysterectomy

While hysterectomy has historically been considered a radical treatment for uterine fibroids, new data on the outcomes of appropriate alternative therapies suggest that these may be similar to hysterectomy in many ways over a controlled period of time. Disadvantages of hysterectomy compared to other alternative therapies include perioperative risks and salpingectomy (if it is part of the procedure). Before the turn of the century, the removal of both ovaries along with a hysterectomy was a common procedure, and large cohort studies in the early 2000s showed that the removal of both ovaries was associated with an increased risk of death, cardiovascular disease, dementia, and other diseases compared with having a hysterectomy and keeping the ovaries. Since then, the surgical rate of salpingectomy has declined, while the surgical rate of hysterectomy has not.

Multiple studies have shown that even if both ovaries are preserved, the risk of cardiovascular disease, anxiety, depression, and death after hysterectomy is greatly increased. Patients ≤35 years of age at the time of hysterectomy are at greatest risk. Among these patients, the risk of coronary artery disease (after adjusting for confounders) and congestive heart failure were 2.5 times higher in women who underwent hysterectomy and 4.6 times higher in women who did not undergo hysterectomy during a median follow-up of 22 years. Women who had a hysterectomy before age 40 and kept their ovaries were 8 to 29 percent more likely to die than women who had not had a hysterectomy. However, patients who had undergone hysterectomy had more comorbidities, such as obesity, hyperlipidemia, or a history of surgery, than women who had not undergone hysterectomy, and because these studies were observational, cause and effect could not be confirmed. Although studies have controlled for these inherent risks, there may still be unmeasured confounding factors. These risks should be explained to patients considering hysterectomy, as many patients with uterine fibroids have less invasive alternatives.

There are currently no primary or secondary prevention strategies for uterine fibroids. Epidemiological studies have found a variety of factors associated with a reduced risk of uterine fibroids, including: eating more fruits and vegetables and less red meat; Exercise regularly; Control your weight; Normal vitamin D levels; Successful live birth; Use of oral contraceptives; And long-acting progesterone preparations. Randomized controlled trials are needed to determine whether modifying these factors can reduce risk. Finally, the study suggests that stress and racism may play a role in the health injustice that exists when it comes to uterine fibroids.