Uterine fibroids (UFs)—benign monoclonal tumors protruding from myometrial smooth muscle cells—are the most common pathology of the female genital tract [1
]. The morphology of UFs may vary greatly. They can be solitary or appear in multiple clusters. Also, their size range is considerable, too, from miniscule to giant masses of over 20 cm in diameter. UFs affect 25–80% women, depending on the population and the risk factors [2
]. The majority of UFs are asymptomatic, and menopause generally results in tumor atrophy, but the symptomatic tumors constitute a major problem for the vast number of affected women. The wide range of UF-associated symptoms includes iron deficiency anemia, abdominal and pelvic pain, gastrointestinal disorders, dysuria, female infertility, and severe obstetric complications [2
This pathology varies greatly in relation to age. These tumors are more prevalent among older populations [2
]. UFs are not observed in pre-pubescent girls and are a rare finding in adolescents, indicating that they depend on hormonal changes [7
]. According to the available data, the growth of UFs depends mostly on the influence of steroid hormones [1
]. Estrogens have been known to play an important role in the pathophysiology of UFs, but the latest research has suggested progesterone as the main factor initiating pathological uterine muscle differentiation and abnormal growth [1
]. The main mechanism of progesterone-induced UFs tumorigenesis consists of an increase in the concentration of selected growth factors [1
]. Also, a significant part of UFs occurs due to a genetic abnormality [1
]. In patients with positive family history, the risk for developing UFs approximately 4 times higher than in the general population [14
]. According to a study by Makinen et al., specific mutations within the gene encoding the mediator complex subunit 12 (MED12
) were detected in the examined UFs [15
]. Nowadays, it is a known fact that even up to 80% of UFs have a mutation in MED12
UFs are a major public health problem. By the age of 50, they might develop in almost 80% and 70% of the African-American and the Caucasian women, respectively [3
]. The effects of UFs on the quality of life (QoL) and the overall cost of treatment are significant but often remain unaddressed or marginalized [17
]. As far as QoL for women in general is concerned, Soliman et al. have recently demonstrated that women who rated their UF-related symptoms as “severe” had significantly worse QoL as compared to their peers with mild symptoms [18
]. QoL deteriorated considerably with the increasing number and severity of symptoms [18
]. A 2015 review of the literature on direct and indirect costs of UF management revealed that substantial sums of money are generated by UFs [19
], and included not only the price of medicines, medical staff salaries, or the cost of surgical treatment, but also the hidden costs of work absence, hospitalization, control visits, and preoperative diagnostic tests. The annual direct and indirect costs of UFs in the United States have been estimated to be between $
9.4 billion [3
], and $
17.2 billion, respectively [20
]. In the United States, the total cost of treatment of a single patient with UFs ranges from $
11,700 to $
25,000 per year after the diagnosis or surgery [19
]. According to a well-known study by Cardozo et al., the total annual cost of UF treatment in the United States has been estimated at $
34.4 billion [20
Tumor size and location determine the occurrence of symptoms, the need for treatment, and the treatment method. Other important determinants include symptom severity, patient age and reproductive plans, the risk for malignancy, skills and expertise of the gynecologists and access to proper medical equipment [2
]. Due to the benign nature of UFs, treatment resulting in the least morbidity and lowest risk should be chosen, if possible [2
]. Multiple UF management options are currently available but surgery remains the method of choice and is often accompanied by pharmacological treatment or pretreatment [2
]. The most common complaint—menorrhagia—is managed with surgical procedures like ablation, myomectomy or uterine artery embolization or, more recently, by pharmacotherapy [6
]. The available treatments for UFs, including hysterectomy, myomectomy, embolization, and gonadotropin-releasing hormone (GnRH) agonists, are effective but are recommended in more advanced stages of the disease, especially since they are neither low-cost nor free of risk for adverse events [25
]. Ulipristal acetate (UPA), a selective progesterone receptor modulator (SPRM), is the most common UF pharmacological treatment [6
]. Clinical trials have demonstrated that UPA is effective for controlling UF-related excessive uterine bleeding and reducing fibroid size [6
]. Treatment schemes with UPA have recently become the gold standard in modern management of UFs [27
]. In those schemes, UPA is administered as first-line therapy to prepare UFs for surgery or, in case of good response, to lead to a condition when surgical treatment is no longer necessary [6
]. However, UPA is relatively expensive and not accessible to everyone, nor is it a substance which can be widely used in prevention [2
]. In spite of the ongoing research, the currently available pharmacological therapies are short-term, to avoid the risk of chronic hormonal therapy, and are accompanied by long-term adverse side effects.
One of the major problems associated with UFs is that they are understudied, and therefore, much research is needed in this field [25
]. The development of UFs is multi-factorial in origin, thus specific methods of prophylaxis are currently unavailable. Various recent attempts to create an inexpensive, safe, and effective drug for the prevention and treatment of UFs are still in the early stages of the process [31
]. Still, several treatments and prophylactic methods can be used in this endeavor [31
]. Current findings suggest that substances contained in green tea [32
], vitamin D [25
], elagolix [34
], paricalcitol [35
], gestrinone [36
], and others may become future preparations for chronic treatment with minimal or moderate side effects. Similar concepts are discussed in an attempt to create a specific method of prophylaxis of UFs in high-risk subjects [14
]. High costs and low efficacy are the key points in UF therapy. If more such substances are known, it will be possible to investigate them further (new dosages and schemes), and combine their effect with the known agents to achieve better performance. This, in turn, may have a great impact upon the health of millions of women in the future.
This publication presents current data about lesser-known substances which may have a beneficial effect on the treatment or prophylaxis of UFs and can be administered orally, serving as an alternative to (or complement) surgery or SPRMs.
2. Materials and Methods
This article presents an up-to-date review of publications regarding the current role of alternative agents in UF treatment and prophylaxis. A literature search was conducted in PubMed of the National Library of Medicine using the following key words: “uterine fibroid”, “pharmacotherapy”, “vitamin D”, “vitamin D analog”, “paricalcitol”, “gestrinone”, “elagolix”, “aromatase inhibitor”, “epigallocatechin gallate”, “green tea”, “curcumin”, and “cabergoline”. The above keywords were selected to reflect possible oral agents in the prophylaxis and therapy of UFs. During our search, we combined the key words into pairs, which resulted in: “uterine fibroid” and “pharmacotherapy”—1694 publications; “uterine fibroid” and “vitamin D”—40 publications; “uterine fibroid” and “vitamin D analog”—2 publications; “uterine fibroid” and “paricalcitol”—2 publications; “uterine fibroid” and “gestrinone”—19 publications; “uterine fibroid” and “elagolix”—1 publication; “uterine fibroid” and “aromatase inhibitor”—73 publications; “uterine fibroid” and “epigallocatechin gallate”—7 publications; “uterine fibroid” and “green tea”—8 publications; “uterine fibroid” and “curcumin”—4 publications; “uterine fibroid” and “cabergoline”—4 publications. If the search was duplicated the papers were excluded. The aim of the review was to critically evaluate the current data about lesser-known substances which might have a serious impact on UFs and UF-related symptoms and which can be administered orally. The results of the available studies in English, published up to October 2017, have been discussed in this article. Additional important and impactful articles and reviews were considered, when relevant. Articles were excluded if they were published in languages other than English. After reviewing the titles and abstracts, approximately 150 full articles have been evaluated.
UFs constitute a serious health problem for many women of reproductive age, as well as those approaching, or actively in, menopause. Prophylaxis of UFs is practically non-existent, while treatment is often costly and expensive. Surgery is standard in symptomatic UF treatment. UPA has been available for several years. Other forms of treatment are not accepted by patients. In the case of more effective agents, the main problem is the chronic use of drugs and the related side effects. In the case of other agents, their poor effectiveness remains the greatest issue. In our opinion, additional solutions are necessary to create appropriate schemes of pharmacological treatment for different groups of women (obese or non-obese, Caucasian or African-American, pre- or post-menopausal, etc.).
Early prevention and treatment of UFs in women from high-risk groups should be our priority. Innovative forms of UF management are under intensive investigation and may be promising options in the near future. There are several studies about the role of the abovementioned agents in UF prophylaxis and therapy in humans. Many of them evaluated vitamin D, paricalcitol, EGCG, elagolix, AIs, and cabergoline and deemed them safe and effective. The next step in such projects should be properly constructed RCTs, carried out by successive phases. However, the agents on the current list had only one registered trial [101
], or none at all. In the case of further positive observations, these agents could become the new generation of drugs in the treatment of UFs, even in the era of UPA.
Perhaps the future solution will be to identify high-risk groups before the onset of UFs and implement preventive methods on the basis of the presented literature. Vitamin D and green tea extract might be optimal in such cases. Recent attempts to create a new, cheap, safe, and effective drug for the treatment of UFs remain in the very early stages, and their success has not been yet determined. Recent findings suggest that substances such as paricalcitol and elagolix may be the formulas for the future as they have minimal or moderate side effects and high levels of efficacy in UF therapy.