Uterine leiomyomata: the snowball effect

Uterine leiomyiomas (ULs) are the most common reproductive-tract benign monoclonal tumors in women and represent one of the leading causes of hysterectomy. They are composed of disordered smooth-muscle cells with large amounts of altered extracellular matrix¹. It is estimated that up to 77% of all women will develop UL during their lifetime. By the age of 50, fibroids have a cumulative incidence of 70% and the prevalence increases up to 90% in black women². ULs are steroid hormone-responsive tumors that show increased expression of estradiol, aromatase, progesterone receptors and estrogen receptor-α. Beyond this hypersensitivity to sex steroid hormones, they also seem to have lost the cyclical regulation by estrogens during the luteal phase when, normally, the myometrium becomes quiescent³. Furthermore, prepubertal exposure to environmental estrogens represents one of the major risk factor for the development of ULs. Indeed, the so-called estrogen-like endocrine disrupting chemicals (bisphenol-A, diethylstilbestrol, dicholodiphenyltrichloroethane, genistein, dioxin, polychlorinated biphenyls), given their structural similarity with natural estrogen, could reprogram the endocrine system resulting in early onset of puberty, disrupted reproductive organ development and hyper-responsiveness to normal estrogen hormone in adult life⁴. Parity, race and lifestyle choices (obesity, smoking, diet) are other UL risk factors. UL incidence decreases with the number of live births and, on the other hand, increases with body weight. In fact, Lumbiganon and colleagues estimated a 6% increase in ULs for each BMI unit increase⁵. Concerning race, black women appear disproportionately affected, with higher incidence rate, larger tumors and more severe symptoms when compared to white women⁶.

Although not all ULs are symptomatic, 15–40% of all affected patients experience a variety of symptoms and will request treatment due to symptoms. Fibroids could cause pelvic discomfort, heavy menstrual bleeding, symptomatic anemia and reproductive dysfunction, ranging from infertility to recurrent pregnancy loss and preterm labor. Larger tumors may cause abdominal distention and pressure symptoms (bulky symptoms) with possible intestinal and urinary dysfunction (urinary incontinence, urgency, increased daytime urinary frequency, hydronephrosis), interfering with quality of life⁷. Despite the general benign nature of ULs, for many women they represent a chronic disease with a heavy impact on daily activities. The emotional burden is also significant. The unpredictability of their menses makes these women anxious, frustrated and worried about their overall health. The strong psychological distress they have to live with is, most of the time, characterized by a sense of helplessness in managing their condition. They fear heavy bleeding accidents and feel “not in control” of their lives⁸.

Additionally, many women express some concerns about their body image. They are often bothered about appearing pregnant and overweight and sometimes report that this condition negatively affects their sexuality and consequently their relationship with their partner. Some women also confess that they lacked satisfactory support from the health care system to help them to cope with these issues, expressing in extreme cases the need to receive psychological support⁹.

To date the available data concerning the management of fibroids is scarce. At present, in fact, there are only few published randomized trials that have compared different therapies for ULs and data on long-term outcomes (quality of life, fertility, recurrence of symptoms, complications) is still inadequate. Current management strategies include both surgical and medical options, depending on severity of symptoms, tumor number, location and size, patient’s age and fertility preservation wishes. Furthermore, current available treatments for ULs to preserve fertility are not capable yet of controlling symptoms and progression of the disease and have not been proven to be effective in the long term or are associated with high risk of post-operative complications and relapse of the disease. Treatments that offer long term resolution are often invasive and burdened by considerable costs related to surgery and hospitalization. To date hysterectomy (laparoscopic or laparotomic) is still considered the standard surgical treatment for symptomatic patients who have already completed their childbearing desire or do not wish to conceive or those of premenopausal age. Uterus-sparing surgical approaches include hysteroscopic myomectomy for small submucosal fibroids, laparoscopic or laparotomic myomectomy (depending on fibroids’ location and size), laparoscopic cryomyolysis and thermo-coagulation and laparoscopic occlusion of the uterine arteries. Other minimally invasive but non-surgical alternatives are uterine artery embolization (UAE), vaginal occlusion of uterine arteries and high frequency magnetic resonance guided focused ultrasound (MGrFUS)¹⁰. For patients who do not desire surgery, recent advances in medical treatment have opened up new conservative options. Gonadotropin-Releasing Hormone (GnRH) agonists have been used for years to reduce fibroids and restore hemoglobin levels, but their use is limited to short periods due to their side effects related to the induced hypoestrogenism (hot flushes, bone loss)¹¹. Lately, the crucial role of progesterone pathways in the pathophysiology has gained attention due to the introduction of selective progesterone receptor modulators (SPRMs) in the treatment of fibroids. SPRMs are synthetic compounds that interact with progesterone receptors. The subsequent activation of coactivators and/or corepressors determines whether an SPRM acts more as an agonist or antagonist¹². They also act on the pituitary gland, inducing amenorrhea by inhibiting Luteinizing Hormone (LH) surge and ovulation and maintaining mid-follicular phase levels of estradiol. A direct action on fibroids reduces their size through the inhibition of cell proliferation and the induction of apoptosis^13,14. In a recent Cochrane review a short-term use of SPRMs resulted in controlled uterine bleeding and reduced pelvic pain and pressure¹⁵. Furthermore, long term intermittent administration of SPRMs may open up new treatment perspectives. In 2016, Donnez and colleagues investigate the efficacy of four repeated 12 week courses of either 5 or 10 mg of ulipristal acetate (UPA) reporting higher amenorrhea rates, significant fibroid volume reduction and improved quality of life when compared to single course treatment¹⁶. SPRMs have expanded the medical options to both treat symptoms and eventually to eliminate or just delay the need of surgery¹⁷. Future research on this topic should focus on prevention strategies, tailored for women genetically predisposed to this condition (e.g. patients with a positive family history) or directed to patients of a young age in order to avoid recurrence after surgery.

ULs represent a worldwide significant public health concern with annual related costs as high as several billion of dollars. Indeed, women diagnosed with ULs are more likely to miss work and experience high risk pregnancies. Absenteeism and short term disability from fibroids are important components of indirect UL-related costs (costs of lost work) and work out to be almost equivalent to direct healthcare costs. Annual healthcare costs associated with the diagnosis of ULs mostly come from inpatient care¹⁸. Minimally invasive options, such as UAE and MGrFUS, are still underperformed and hysterectomy for ULs remains one of the most frequent surgical interventions that involve inpatient hospital stay (broadly 2–3 days). Moreover, considering that the total number of hysterectomies for fibroids is higher than the number of hysterectomies performed for any type of gynecological cancer, it is easy to understand that costs related to UL treatment represent an important issue for the health care system. Indeed, nowadays, the total health care cost and the cost for inpatient care in women with fibroids are 2.6 times and 6.6 times higher than those for women without fibroids. It is also important to consider that the number of uterus-sparing surgeries (e.g. myomectomy) is expected to increase in the upcoming years due to the tendency of many women to postpone childbearing or to prefer less invasive treatment options. This type of surgery is, in fact, often preceded and/or followed by medical treatment or is due to the relapse of the disease by additional surgical interventions (myomectomy, hysterectomy) thus increasing the total per-person cost for fibroid related care. Other additional costs (pregnancy complications, infertility treatments) are also substantial¹⁹. Wechter et al. tried to create predicted scenarios for the coming decades, considering growing population and projected racial changes. They estimate that UL-related hospitalizations will increase 23% by 2050, with a 20% and 31% increase in hysterectomies and myomectomies for ULs²⁰.

In conclusion, symptomatic uterine leiomyomata remain a very important topic in women’s health. Given their often-devastating impact on quality of life, leiomyomas are also a primary source of consumption and inpatient care and major surgeries are still considerable, despite new less invasive surgical and non-surgical alternatives. Future research is required to encounter a successful approach to managing fibroids that includes medical, surgical and psychological strategies that can fully support the women living with this chronic condition.

Transparency

Declaration of funding

This editorial did not receive any funding.

Declaration of financial/other relationships

I.S. and R.M. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this editorial have no relevant financial or other relationships to disclose.