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To review currently available literature regarding biology, risk factors, symptoms, pathogenesis, and therapeutics of uterine leiomyoma. Extensive literature review of 200 articles aiming towards uterine leiomyoma. Uterine leiomyomas are solid abdominal monoclonal tumours mostly develop in myometrium of uterus and adversely affect endometrium. Fibroids in uterus are major cause of morbidity in women. Uterine fibroids also show hereditary effects and reported in women of next generations. Submucosal and intramural fibroids distort uterine cavity, affect implantation and lead to infertility. Mechano-transduction from ECM components to intracellular components of myometrial cells stimulate cytoskeletal shape alterations and enhanced ECM stiffness provide basal node for tumour initiation. Oestrogen and progesterone further regulate development of uterine leiomyoma. Main aim of study is to distinguish uterine leiomyomas with higher efficacy to develop more effective medical treatment. Curcumin, EGCG and many more natural compounds may be considered as potential therapeutic agents and growth inhibitor for leiomyoma. Present review is focussed on biology. Risk factors, symptoms, pathogenesis and therapeutics of uterine leiomyoma. By regulating many cyclin dependent kinases (CDKs) and caspases, cell cycle checkpoints can be altered and fibroid growth be prevented. A comprehensive information has been obtained, although there are many lacunae and mechanism not so well understood. Yet present study may open new window for research for leiomyoma therapeutics.
Department of Genetics, M. D. University, Rohtak, Haryana, India
Minakshi Vashist*
Department of Genetics, M. D. University, Rohtak, Haryana, India
Rohit Kaushik
Department of Genetics, M. D. University, Rohtak, Haryana, India
Vandana Kalra
Goswami Ganesh Dutta Sanatan Dharma College, Palwal, Haryana, India
Reetu Hooda
Department of Gynaecology and Obstetrics, P.G.I.M.S., Rohtak, Haryana, India
Sunita Singh
Department of Pathology, P.G.I.M.S., Rohtak, Haryana, India
*Address all correspondence to: mvashist14@mdurohtak.ac.in
1. Introduction
1.1 Search strategies
A comprehensive literature search was conducted spanning from the initial records up to May 15, 2023, by researchers. The search was executed across prominent databases including PubMed, Google Scholar, and Web of Science. The search strategy was structured into three distinct sections, incorporating Subject Headings terms along with relevant free-text terms related to Uterine leiomyoma, encompassing aspects of pathogenesis and therapeutics. Notably, no constraints were imposed on language, publication date, or any other limiting factors during the search process.
Uterine leiomyomas (known as uterine fibroids) are solid abdominal monoclonal tumours developing in myometrium of uterus and adversely affecting endometrium. Fibroids in uterus are major cause of morbidness in women. Leiomyomas are most common public health problem around world. Commonness of fibroid development in women is age-dependent and by an age of 50 years it has been detected in 80% of women. According to a WHO report, 6.6% of global women (nearly 235 million) population was affected of fibroids [1]. It is most commonly diagnosed in women with age of 30 and 40 years. 70–80% of women are affected by uterine fibroids during their lifetime by age of 50 [2]. 40-60% of all hysterectomies performed in Italy, 39% in United States, and 65% in India annually are indications of fibroids [3]. 30-50% women are symptomatic otherwise remaining detected incidentally by ultrasonography imaging [4]. Fibroid have shown 29% frequency of hospitalisation during 15–54 years of age [5].
In a general context, leiomyomas are comprised of a combination of smooth muscle cells, fibroblasts, and an interstitial matrix that includes constituents such as collagen, proteoglycan, and fibronectin. These elements form a complex structure characterised by the presence of interwoven bundles of lance-shaped or stellate myocytes. Notably, this arrangement exhibits minimal cellular pleomorphism or mitotic activity, as noted in Ref. [6]. The process of leiomyoma formation involves two main components: the alteration of normal smooth muscle cells into abnormal ones and their subsequent transformation into distinct tumour nodules [7]. Leiomyoma may be solitaire or multiple tumour nodules within same uterus surrounded by different quantity of interstitial fibrous connective mesodermal tissue. Leiomyomas development is directly influenced by increased exposure of steroid hormones. There is slow proliferation of fibroid myometrial cells with deposition of ECM (especially excessive collagen deposition) generally in steroid-hormone-dependent manner [8]. Size of fibroids can vary from large sized totally filling whole uterine cavity to small sized in millimetre, centimetres or microscopic [9].
Uterine fibroids are diagnosed by imaging ultrasonography, sonohysterography, X-ray examination, magnetic resonance imaging and by histological evaluation. Most common symptoms observed after uterine fibroids development are menorrhagia, pain in pelvic region, infertility, heavy bleeding during menstruation, anaemia, constipation, urine incontinence etc. [10]. Increased micturition, incontinence and obstruction of the ureter are symptoms associated with urinary tract. Blockage of the ureter, which can result in hydronephrosis, necessitates prompt treatment. Additionally, the presence of symptoms related to the gastrointestinal tract, such as constipation and tenesmus (characterised by the recurrent urge to defecate), can often be attributed to the development of fibroids [11].
Fibroids development in uterus results in distorted uterine cavity hence resulting in failure of implantation and pregnancy [12]. Pregnant women affected by fibroids experience a higher incidence of complications during pregnancy. These complications include preterm delivery (16.7% compared to 6.3%), premature rupture of membranes (14.3% compared to 2.1%), placental abruption (7.5% compared to 0.9%), foetal malformation (6.2% compared to 3.3%), postpartum haemorrhage (33% compared to 6%), and fatal malpresentation (19% compared to 4.4%), when compared to women who do not have fibroids [13]. Shoulder dystocia, postnatal bleeding, ectopic pregnancy, or miscarriage are other complaints associated with fibroid development during pregnancy. Fibroids represents 10% of infertility cases in women [14]. Symptoms severity and manifestation time directly depends on fibroids location in uterus. For example, when compared with subserosal fibroids, submucosal fibroids result in more irregular uterine bleeding and pregnancy problems [15].
Pre-menstruation, obesity, parity, fatty acids rich diet, smoking, caffeine and alcohol are some of risk factors for developing fibroid [5]. Fibroids can also develop to women having genomic syndromes like Alport syndrome, Cowden syndrome, reed syndrome etc. [16]. Uterine fibroids also show hereditary effects and most likely effects women of next generations.
Leiomyomas are of monoclonal origin i.e. originate from single myometrial cell. Two leiomyomas within a single uterus can vary in their molecular-genetical background. Identification of genetical mechanisms of leiomyoma concerning cellular differentiation of myocytes is still under research and not well known. But there are evidences of involvement of genes like oestrogen receptor (ER) gene, progesterone receptor (PR) gene, high mobility group (HMG) genes, fumarate hydratase (FH) gene, mediator sub-complex (MED) gene and collagen type-IV genes (COL4A and COL5A) which influences genomic instability [17]. Many genes in cell proliferation, differentiation and ECM production are dysregulated in uterine leiomyomas. These genes may be effectors or promoters of uterine leiomyomas growth. Regulation of gene expression is dependent on gonadal steroid hormones level variations during different phases of menstrual cycle. Fibroid develops between menarche and menopause [8]. Most fibroids shrink after menopause. Hysterectomy, myomectomy and uterine artery embolization are the commonest medical treatments used for curing fibroid development [18].
There are several exogenous and endogenous risk factors associated with uterine fibroids. These are age, race, early menarche, genetic factors, hormonal factors, stress, obesity and other factors such as diet rich in red meat, high blood pressure, hypertension, family history, caffeine intake etc.
2.1 Exogenous risk factors
2.1.1 Diet
Diet plays critical role in uterine fibroid development. Eating habits of different countries explain different frequencies of leiomyoma. Endogenous hormone metabolism gets modified due to variation in dietary components.
Dairy products: higher composition of fatty acids of animal origin increases risk of fibroid development rather than of dairy origin. Dairy product consumption decreases fibroid development risk in a dosage-dependent manner. A 33% decreased risk of fibroid development was observed in women with ≥4 intake of dairy product per day compared with those having no or less serving per day [19].
Red meat: red meats and beef consumption increase fibroids risk whereas fish consumption shows a decrease risk [20].
Fruits and vegetables: an inverse association is also observed in between uterine fibroids and high fruits and vegetable consumption especially tomatoes, apples, citrus fruits and cruciferous vegetable. These dietary components decrease risk of fibroid commonness by inhibiting rapid proliferation, programmed cell death and hormone dependency [21].
Vitamins: vitamin D supplemented diet also reduces fibroid development as vitamin D3 acts as an antitumor agent inhibiting cell proliferation [22]. Vitamin D3 also acts as an anti-estrogenic agent and reduces steroid hormone receptor expression making it a novel therapeutic option for uterine fibroid treatment [23]. An inverse relation has been observed in between Vitamin A derived from animal product and fibroid development [21]. Vitamin A gets transformed into more effective compounds like retinoic acid that shows inhibiting efficiency in leiomyoma expansion in vitro. No significant relationship has been observed in between Vitamin C and E dietary intake and fibroid risk [24].
2.1.2 Smoking
Smoking and uterine fibroid risk association are controversial [25]. Smoking reduces circulating oestrogen levels by inhibiting aromatase activity which is responsible for conversion of androgen to oestrogen, therefore decreasing oestrogen bioavailability [26]. In contrast, smoking also exerts oestrogen related effect on uterus promoting cell proliferation [27]. Therefore, effect of smoking on fibroid remains under conflict.
2.1.3 Alcohol
Alcohol increase fibroid development risk. BWHS examined risk association in regard to alcoholic beverage types [28]. An increased relationship of beer (having greater content of phytoestrogen) consumption has been found rather than in wine [25].
2.1.4 Caffeine
Huge coffee intake is a risk for younger women and not for women of all ages [20]. Caffeine intake stimulates early follicular phase oestradiol level [29] and also increases sex steroid production and phosphodiesterase inhibition [30]. Caffeine exerts negative effect only when consumed greater than 500 mg per day [31].
2.1.5 Endocrine disruptors
Endocrine Disruptor Chemicals (EDCs) present in pharmaceuticals, plasticizers especially DES (Diethylstilbestrol), dioxins, biphenyls, phthalates and organochlorines are sensitive to uterine fibroid development. High dioxin serum level shows a reduced fibroid risk [32]. DES increase tumorigenesis [33]. Mechanism of EDC exposer which increases tumorigenesis is quiet under research.
2.1.6 Exercise
Exercise induces a protective effect on fibroids. Women exercising regularly have lower risk of fibroids in comparison to those who do not do exercise [34]. Physical activity reduces sex steroid hormones circulation, insulin levels and availability of free circulating oestrogen by increasing SHBG levels. A reciprocal relationship between physical activities and fibroids presence has been observed [35]. This study also reveals a dose-dependent response i.e. women performing high level of physical exercise have less commonness level of fibroids then who performs fewer physical activities (≥7 h per week vs. <2 h per week). Benign uterine tumours develop 1.4 times more likely in non-athletic women than athletic women [25].
2.1.7 Stress
Stress plays important role in pathogenesis of uterine fibroids. Greater risk of fibroid development depends on larger count of vital life incidents and stress intensity [36]. The NHS II found a higher uterine leiomyoma prevalence in between women who are long-serving to ill-treat in their early-stages of life. The risk was lesser among women appearing in an emotionally supportive relationship in their teenage which recommend that the emotional and social support can diminish the influence of stress on risk [37].
2.2 Endogenous risk factors
2.2.1 Age
The primary and most significant risk factor for the development of uterine fibroids is age. The occurrence of leiomyomas has not been documented before adolescence, and their frequency diminishes notably after menopause [14]. With advancing age, the likelihood of developing fibroids significantly escalates, resulting in a substantial increase in both frequency and quantity of fibroids [38]. Moreover, the rate of hospitalisation due to uterine fibroids follows an age-related pattern. It reaches its highest point at 62.7 per 10,000 women within the age range of 45–49 years. Subsequently, this rate gradually declines to 31.8 per 10,000 women within the age range of 50–54 years [39].
2.2.2 Race
Lifetime risk for uterine fibroid (aggregated risk of fibroid development by 50 years of age) have been reported more in black women (78%) [14]. Black women develop fibroids 10 years before when compared to white women. The prevalence of uterine fibroids is noteworthy among different racial groups. Among African-American women, the occurrence of fibroids in the uterus reaches 60% by the age of 35, and this percentage rises to 80% by the age of 50. In contrast, white women have a lower incidence of fibroid development, with approximately 40% affected by age 35, which then increases to nearly 70% by age 50 [40]. Notably, uterine fibroids in black women are often characterised by being numerous and larger in size. Additionally, these fibroids tend to manifest more complex and severe symptoms in comparison to those experienced by white women [28].
2.2.3 Obesity
Obesity is considered as a risky factor for fibroids development in uterus. An increase in body mass index (BMI) is directly correlated with increased fibroid risk [34]. Risk increases 20% with every 10 kg increase of weight [41]. It may act through hormonal or through inflammatory mechanism. Obesity increases conversion rate of adrenal steroid hormones into oestrogen and reduces production of sex hormones binding globulin (SHBG) from hepatic cells, resultant being higher amount of free active oestrogen [34]. Fibroids presence in uterus was higher in case of visceral fat and peritoneal fat thickness. However, subcutaneous fat thickness does not show any significant association with fibroids presence [42].
2.2.4 Reproductive factors
Pregnancy and parity: pregnancy showed a protective effect on fibroid development. High parity (3 or more deliveries) decreases fibroid risk up to five times [43]. Growth of fibroid is affected by sharp elevation during very early pregnancy and decline postpartum period of oestrogen and progesterone. Fibroid that develops during first trimester of pregnancy get reduced in diameter by 0.5 cm. However high parity and less leiomyoma commonness are assumed over estimated as fibroid existence leads to infertility therefore reduces parity itself [31].
Early menarche: an inverse association was found in between early age menarche and fibroid risk [44]. Menarche at an early age i.e. before age of 10 years is associated with higher risk of developing fibroids. Early menarche is accompanied with increased oestradiol to post-pubertal levels which can probably lead to increase in fibroid growth [45]. This may describe that generally black patients have earlier menarche than in white patients which show that black patients have early onset of disease [46].
2.2.5 Family history
Uterine leiomyomas is a hereditary disease and tend to run in families. Family history of women with fibroids has been reported. Mutation in a single myometrial stem cell in uterus (existing from birth) is believed to be responsible for fibroid formation. Fibroid have monoclonal development i.e. arises from a single cell abnormality, but it is unknown what triggers the change from a normal to an aberrant myocyte [47, 48]. Numerous researches have shown that fibroid exhibit specified gene-directed chromosomal abnormalities [49]. Whatever causes the transition of a normal myocyte into an aberrant one, it is more frequent or more powerful in families where fibroids are more common, resulting in twice as many of these tumours as in families where fibroids are caused by somatic changes. Some fibroids may manifest as a result of inherited genes and so have a family frequency, whereas others may manifest as a result of acquired gene mutations [50].
2.2.6 Genetic factors
Fibroid growth and development is directly enhanced by genetic abnormalities. Whole genome sequencing and gene expression profiling of different uterine leiomyomas and neighbouring myometrium was performed [51]. MED12, HMGA2, FH and many other genomic abnormalities were observed which acts as genetic hits for uterine fibroid development. The accurate racial inconsistency in uterine leiomyoma commonness and increased familial aggregation of uterine fibroids specifies that molecular level factors are also basis of fibroid formation. Pathology data (especially in larger tumours) show non-random chromosomal abnormalities that are related to mutations in cell growth regulation. These chromosomal abnormalities are preceded due to clonal expansion of leiomyoma cells, indicating that chromosomal abnormalities also effects growth [52]. Familial aggregation of fibroids has been reported [53] and studies in mainly white women populations have reported cross-product ratios of 2.2–4 for female relative of women having leiomyoma to develop the condition [54].
The cellular origin of uterine fibroids remains a subject of ongoing debate and uncertainty within the scientific community. However, several studies provide support for the notion that each fibroid originates from the transformation of a single myometrial stem cell, driven by the influence of ovarian steroid hormones. These fibroids are considered monoclonal tumours, originating from a single cell with genetic alterations [55]. Human myometrial tissues comprise somatic cells exhibiting multipotent characteristics. Under the influence of ovarian hormones, these myometrial tissue cells engage in asymmetric division, leading to self-renewal and the generation of daughter cells responsible for tissue regeneration [56]. It’s worth noting that fibroids in the human uterus possess fewer stem cells compared to normal myometrium. Interestingly, stem cells derived from fibroid tissue, as opposed to those from normal myometrium, are found to carry mutations in the MED12 gene (mediator complex subunit 12). This genetic alteration suggests a significant genetic event that transforms the myometrial stem cell, resulting in a coordinated interaction with neighbouring myometrial tissue and ultimately culminating in the formation of a fibroid tumour [57].
3.1 Mechano-transduction
Hormonal stimulation is an essential factor for tumour growth but non-hormonal factors such as hypoxia, repeated myometrial damage, repair and changes especially muscular contraction during pregnancy, childbirth and menstruation, chronic inflammation and extravasation of menstrual blood into myometrium may be responsible for fibroid initiation [58]. Chronic inflammation can also act as a major factor as it increases vascularization, vascular permeability and fibroblast proliferation [7]. Abnormal inflammatory response could be produced due to menstrual damage. Ischemic damage, resulting from reperfusion after ischemia in the myometrium, might be initiated by the contractions of the myometrium during menstrual bleeding. Cells within the myometrium that are affected by this damage could potentially transform into uterine fibroid progenitor cells. These cells may undergo apoptosis and be eliminated during the follicular phase, or if they manage to survive, they might develop mechanisms that shield them from oxidative stress and apoptosis, leading to their differentiation into uterine fibroid progenitor cells [59]. Frequent damage occurring within the myometrium and its adjacent extracellular matrix (ECM) components gives rise to a state of mechanical stress. The ECM plays a direct role in orchestrating irregularities in tumour composition, structural arrangement, fluid distribution, and firmness. Consequently, these aberrations escalate the mechanical stress encountered within the tissue. This escalated mechanical stress serves as a trigger for the transmission of mechanical signals (mechano-transduction) through collagen and other ECM constituents. These signals travel through transmembrane receptors, prompting modifications in cellular behaviour and the cytoskeletal framework. As a result, the heightened stiffness of the ECM further intensifies, setting the stage for the initiation of tumours by establishing a basal node in the process [60]. ECM components such as collagen, fibronectin and proteoglycans show abnormalities both qualitatively (altered and unordered composition) and quantitatively (two-fold excessive deposition) in uterine leiomyomas. These altered components act as a source for growth factors, cytokines, inflammatory and angiogenic mediators and proteases. Leiomyoma shows abnormal fibroblast structure and orientation. Focal adhesions get formed by clustering and activation of integrin receptors. This further leads to activation of FAK (focal adhesion kinases) which activate MAPK and PI3K pathways, altering cell cycle regulatory proteins and enhancing proliferation [61]. As compared to myometrium, type I and III collagen mRNA and type I and V collagen proteins are higher in fibroids. Both autocrine and paracrine processes regulate fibroid growth [7]. Uterine fibroids develop in between menarche and menopause. A lot of chances are present in between for any genetic hit to develop fibroid.
3.2 Initiation of tumour formation
Normal myometrial tissue containing pool of stem cells showing self-renewal ability and controls proliferation of normal myometrial myocytes under steroid hormone (oestrogen and progesterone) influence. Mature myocytes show much more oestrogen receptor α (ERα) and progesterone receptor (PR) expression then stem cells. So, sex hormones dependent cell proliferation is regulated by steroid hormone receptors present on these mature cells [62]. Self-renewal and proliferation of stem cells is induced by paracrine factors like WNT ligands, released from mature myocytes. Molecular strike like MED 12 mutation or chromosomal abnormality may changeover a myometrial stem cell into a fibroid stem cell [7]. Such fibroid cell with a genetic hit self-renews and divides in uncontrolled manner until differentiates into mature fibroid myocyte (Figure 1). Along with this, fibroid myocyte also gains other epigenetic and phenotypic anomalies. Steroid hormone receptors exhibit robust activity within mature fibroid myocytes, translating steroid hormone signals to stem cells through paracrine mechanisms. A solitary converted fibroid stem cell can initiate the development of a benign fibroid tumour characterised by well-defined boundaries, which progressively grows within the myometrial tissue. The creation of the extracellular matrix (ECM) also plays a role in facilitating the expansion of the tumour [63].
Figure 1.
Tumorigenesis of fibroids: normal myometrium contain stem cells for regeneration during menstruation, pregnancy etc. mature myometrium cells have higher levels of ER and PR expression than stem cells. After binding of oestrogen and progesterone to their respective receptors, they induce paracrine interactions to nearby stem cells and induces cell proliferation and self-renewal. Genetic alteration such as MED12 mutation transforms myometrial stem cell into fibroid stem cell. Many genetic and epigenetic changes stimulate their transformation. These fibroid cells self-renew and proliferate uncontrollably and at last differentiate into mature fibroid smooth muscle cell. ER and PR higher expression in mature fibroid-stem cells again paracrinely induces immature cells for division. ECM excessive deposition further contributes to tumour growth. In this way, single transformed fibroid stem cell forms fibroid tumour with well outlined boundaries. Courtesy by Bulun [63].
3.3 Growth of tumour
In vivo experiments reveal that human fibroid tumours growth require presence of multipotent somatic stem cells depending upon levels of oestrogen and progesterone. Fibroids stem cells as compared to myometrial cells express significantly small level of steroid hormones (oestrogen and progesterone) receptors. However, fibroid stem cells growth essentially requires myometrial cells along with excess levels of steroid receptors as well as their hormones i.e. oestrogen and progesterone. Oestrogen and progesterone action on leiomyoma stem cells is regulated by uterine involuntary myometrial cells in paracrine fashion. This cell-to-cell vicinity interaction with neighbouring cells supports fibroid stem cells self-renewal [64]. Signalling by Wingless type protein (WNT)-β-catenin pathway effectively regulate somatic stem cell function in myometrium and uterine leiomyoma tissue. Almost similar levels of β-catenin were observed in myometrium and fibroid tissue [65]. But as effects of β-catenin are influenced at stem cells level, its level was not of much difference when compared to both myometrium and fibroid cells. Targeted depletion of β-catenin within the uterine myometrium leads to a reduction in uterine dimensions, accompanied by the replacement of uterine tissue with adipose cells. This process disrupts the usual course of myometrial differentiation or myocyte regeneration [56]. Conversely, an excessive presence of β-catenin in the uterine mesenchyme during the embryonic phase results in the emergence of tumours reminiscent of fibroids within the uterus [66]. WNT proteins get secreted and attach to cell-surface receptors of frizzled family, resulting in β-catenin decreased deterioration in cytosol by protein cascade activation. This leads to β-catenin amount variation reaching to nucleus. Due to this escaped degradation, cytoplasmic β-catenin enters nucleus and binds with chromatin and T-cell transcription factor (TCF) family proteins and regulates a number of gene expression and cellular functions like cell destiny, differentiation and tumorigenesis. Ovarian steroid hormone (oestrogen and progesterone) enhances WNT secretion from mature myocytes surrounding stem cells. WNT activates β-catenin-TCF pathway producing TGFβ in mature cells leading excessive ECM formation (Figure 2). MED12 mutation is linked to increased expression of TGFβ receptor activating its downstream signalling involving SMAD and MAPK mediating fibroid stem cell self-renewing and procreation [63]. Interfering with WNT binding or inhibiting β-catenin in leiomyoma stem-precursor cells has a notable effect in curtailing the expansion of tumours [67]. Activation of the WNT-β-catenin pathway spurs the expression of TGF-β3 (Transforming Growth Factor β3), which in turn triggers cell proliferation and the construction of extracellular matrix (ECM) components—particularly the ECM protein fibronectin—in human fibroid tissue, surpassing the levels observed in the myometrium [68]. This TGF-β3 derived from fibroid tissue curbs the expression of local anticoagulant factors within adjacent endomyocytes, consequently leading to prolonged menstrual bleeding—an indicator of its affiliation with fibroids. These findings underscore a significant interplay between the activation of the WNT-β-Catenin pathway, the TGF-β pathway, ovarian hormones, and stem cell renewal, culminating in the formation of uterine fibroid tumours [66].
Figure 2.
Paracrine signalling among oestrogen and progesterone hormones, β-catenin-TGF-β pathways and MED12 in fibroid cells as well as potential role of natural products: oestrogen and progesterone binds to their respective receptors (higher expression) present on fibroid stem cells in paracrine way. This binding stimulates WNT secretion from mature myocytes. WNT further activates β-catenin-TCF pathway and stimulates TGF-β production in mature cells and resultantly excessive deposition. MED12 mutation in stem cells induces TGF-β increased expression and activates downstream signalling by activating SMAD and MAPK proteins enhancing self-renewal and procreation of cells. Natural compounds such as EGCG, lycopene, resveratrol (maintains ECM deposition and its protein formation in a regular manner), berberine, curcumin, fucoidans (suppress increased TGF-β and WNT expression in normal myometrium cells) inhibits myometrium stem cell conversion to fibroid stem cell and inhibits cell proliferation so regulating tumour growth (where TGF-β is transforming growth factor-β; MED12 is mediator subunit complex 12; WNT is wingless-related integration site protein, TCF is T-cell transcription factor, SMAD is mothers against decapentaplegic homologue protein and MAPK is mitogen-activated protein kinase). Courtesy by Bulun [63].
4. Steroid hormones and receptors as main regulators of uterine leiomyoma development
A universal feature of uterine fibroids is its response towards oestrogen and progesterone. Oestrogen and progesterone and their receptors are key regulators of fibroid development.
4.1 Oestrogen and its receptor
Oestrogen simulates uterine fibroid growth through oestrogen receptors. Oestrogen receptors have two isoforms i.e. ERα and ERβ encoded by two different genes—ESR1 and ESR2 respectively, present on chromosome no. 6q25 and 14q23-24.1. ESR1 have eight exons spanning in more than 140 Kbps region. At boundary of intron 1 and exon 2 of ESR1, a well-known T/C SNP recognised by restriction enzyme Pvu II in uterine leiomyoma in South Indian population was revealed. This polymorphism also shows confirmed association in Asian Taiwanese, American and Hispanic population. It also shows association with other reproductive pathologies like ovulatory dysfunction, ovarian cysts, and breast cancer in women revealing its importance in affecting ER functionality [69]. ESR2 also have eight exons spanning in approximately 40 Kbps region. Two different promoters namely, 0 N and 0 K promoters initiate transcription of ESR2 gene. These transcription promoters (mainly 0 N) are involved in uterine leiomyoma pathogenesis as its variation alters ER-β protein levels. ESR2 gene polymorphisms reveal a significant association with uterine leiomyoma in South Indian population [8]. ER are of two types—nuclear and plasma membrane bound (mER and GPR30). 5–10% of total ERs are plasma membrane localised. ERα and ERβ, both isoforms are localised at plasma membrane [70]. By altering transcriptional activity and hastening signal transmission, oestrogen produces its effects. Oestrogen binds to nucleus ER and E2-ER complex regulate transcriptional activities while mER are bounded with heat shock protein 90 (HSP90), also responsible for trafficking in nuclear materials. Binding of E2 to mER results in HSP90 dissociation, dimerization of ER and other conformational changes, resulting in binding of ER to EREs of DNA at target genes promoters [71]. On other hand, E2 binding on mER form homodimers which leads to activation of several kinases, like src which further activate PI3K and ERK pathways. GPR30 activation generates cAMP, Ca2+ release and activation of protein kinase and then transcriptional activation of some specific genes like c-fos, c-Jun etc. [72]. ERα and ERβ expression was noted in both myometrium and fibroid tissue [73]. Transcription is more dominantly activated by ERα and is stimulated by ERβ [74]. Fibroids shows enhanced oestrogen level than neighbouring myometrium and also enhanced aromatase and 17-β hydroxyl steroid dehydrogenase type1 levels [75]. Increased expression of aromatase also enhances fibroid tumorigenesis especially in black women. It has been observed that fibroid tissue from black women have high levels of aromatase than in white women resulting in increased levels of oestrogen in black women fibroid tissue [76]. Aromatase activity in fibroid cells locally increases oestrogen levels, along with it ovarian oestrogen level also get exposed to fibroid tissue [75]. Multiple promoters controlled by transcription factors in fibroid tissue stimulate single aromatase protein expression that transforms circulating steroid hormone precursors into oestrogen [77]. Fibroids are capable of producing sufficient oestrogen in a paracrine fashion to retain their auto-expansion. Gonadotrophin independent aromatase expression in fibroids is still unknown [78]. Aromatase inhibitors effectively shrink fibroid volume suggesting that aromatase inhibition is important regulatory mechanism in fibroid shrinkage [79]. Aromatase RNA expression was not observed in myometrium without fibroids [75]. ERα and ERβ expression in uterine leiomyoma leads to differentiation of fibroid precursor cells [73]. Oestrogen binding to ERα functions in a permissive way enabling tissue to react towards progesterone by enhancing PR expression. Oestrogen increases multiple growth factor, collagen (ESM component), oestrogen receptor and progesterone receptor expression in fibroid pathogenesis [80]. Oestrogen rapidly activates different kind of kinases [81]. Oestrogen stimulates fibroid cells proliferation by ATP-sensitive potassium channels opening. Oestrogen stimulates fibroid expansion by suppressing normal p53 functions [62]. Leiomyoma proliferation requires oestrogen, however it is not adequate on its own [78]. Oestrogen and its receptor, ERα, play a pivotal role in controlling the expression of PR. Notably, oestrogen alone does not function as a mitogen in vivo [62]. Leiomyoma proliferative activity increases with combined oestrogen and progesterone level in postmenopausal women but does not show enhancement alone with oestrogen replacement [82]. Disruption of oestrogen signalling pathway with ERα mutant decreases wild type ERα and PR gene expression [83].
4.2 Progesterone and its receptor
Progesterone is primary maintainer of fibroid extension and volume maintenance while oestrogen mainly induces PR expression [62]. Progesterone shows its effects through progesterone receptors. Progesterone gene receptor (PGR) gene has two isoforms i.e. PR-A and PR-B located on chromosome 11q22-23. Two different promoters transcribe these two isoforms but have same translational site except that PR-B have an additional 165 amino acids [84]. Progesterone acts through PR-A and PR-B showing enhanced level in fibroids in comparison to myometrium [85]. Leiomyoma surfaces exhibit heightened expression of PR-B mRNA. It’s important to note that PR-A is primarily involved in ovulation and governs the anti-proliferative impacts of progesterone within the uterus. On the other hand, PR-B plays a crucial role in the typical development and operation of mammary glands [86] Progesterone and PR were necessary and sufficient for fibroid expansion, as they stimulate cell proliferation, interstitial matrix deposition and cellular hypertrophy [87]. Progesterone receptors are also of two types—nuclear and membrane bound. mPR have three isoforms—mPRα, mPRβ and mPRγ [88]. Pg bounded PR binds at progesterone response elements on DNA and regulates transcription of several genes. PR have proline-rich motif that directly activate ERK-MAPK signalling pathway [89]. It also activates AKT and glycogen synthase kinase-3B (GSK3B). This shows that progesterone stimulates leiomyoma cells proliferation by activating AKT signalling pathway. Secretory phase of menstrual cycle (which is progesterone dominant) shows higher mitotic activity than proliferative phase (which is oestrogen dominant) [70]. ER are activated by PR-B type while suppressed by PR-A type [84]. The progesterone receptor, a transcription factor activated by its ligand (progesterone or anti-progestins), serves as a master regulator of gene expression, overseeing the effects of progesterone and anti-progestins on a multitude of genes [90]. Anti-progestins like RU486 (Mifepristone) bound with PR co-relates with more than 7000 DNA sites and genes encoding in these regions controls cell growths, focal adhesion and ECM functioning [91]. Anti-progestin bounded PR in fibroid cells assembles a transcriptional complex forming bridge between DNA sequence and transcription starts sites of KLF11 (Kruppel-like transcription factor 11) resulting in KLF11 gene and protein expression. In response, KLF11 inhibits fibroid cell proliferation. KLF11 (tumour suppressor gene) is a transcription factor interacts with PR signalling and thus with fibroid cell proliferation [92]. In contrast, progesterone bound PR maintains KLF11 transcriptional repression by same DNA sequence regulation resulting in increased cell proliferation of fibroid. On other hand, progesterone binding to PR increases apoptotic inhibitory BCL2 (B-cell lymphoma 2) protein level by binding with a DNA sequence proximate upstream of BCL2 transcription start site and therefore decreasing apoptosis in fibroid tissue [63].
Both progesterone and oestrogen exert control over growth factors and their corresponding signalling pathways [93]. The activation of steroid hormone receptors leads to the upregulation of growth factors and receptor tyrosine kinases (RTKs), which subsequently operate through the mitogen-activated protein kinase (MAPK) cascade. This intricate process mediates various cellular functions, including transcription, translation, and cell proliferation [94]. Also, progesterone binding to cytoplasmic PR speedily activate extra-nuclear phosphatidylinositol-3-kinase-AKT signalling pathway which increases fibroid cell proliferation and inhibits apoptosis [89]. These two sex hormones interactions with other transcription factors were intricate. Progesterone also shows non-genomic actions such as AKT pathway activation promoting tumour expansion by cell survival stimulation and programmed cell death inhibition [89]. Progesterone upregulate EGF and TGFβ3 expression [68] and LAT-2 level i.e. L-type amino acid transporter-2 and downregulates TNFα expression and IGF1 expression through PR-B while PR-A upregulate it [95]. Progesterone is a more significant regulator of fibroid expansion than oestrogen, according to progesterone receptor modulators (PRMs), which are therapeutically utilised to treat leiomyoma [96].
5. Natural products as therapeutic agents for uterine leiomyoma
Now-a-days studies are focused from steroid hormones affect to fibroid stem cells and genetic abnormalities finding which will result in discoveries of new therapeutic agents like curcumin, green tea, resveratrol, lycopene and fucoidans (Table 1).
Catechins make up 30–42% of the dry weight of the solids in green tea [111]. Epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epicatechin are the four main catechins found in green tea. Catechins are a class of bioflavonoids with anti-inflammatory and antioxidant properties [97]. By altering signalling pathways related to cell proliferation, transformation, infection sensitivity, and oxidative stress, EGCG prevents the growth of uterine fibroids tumours at every stage [88]. EGCG suppress proliferation of Human fibroid cell and enhance programmed cell death. EGCG effectively prevents UF cell proliferation by down-regulating cyclin dependent kinases (CDKs), including CDK2 and CDK4, initiating apoptosis and prevent angiogenesis [98]. Therefore, EGCG may be used as potential future therapeutic agent for fibroid treatment.
5.2 Curcumin
The primary naturally occurring polyphenol in rhizome of curcuma longa is yellow-coloured curcumin. Curcumin has a number of beneficial qualities, including antimicrobial, anti-inflammatory, anti-tumorigenic, and anti-mutagenic. Curcumin reduces endothelial cell fibrosis and inhibits TGF-related endothelial-to-mesenchymal transition. Curcumin has a suppressive outcome on leiomyoma cell procreation and ECM buildup [97]. Curcumin induces apoptosis by regulating key factors such as extracellular signal-regulated kinases (ERKs), caspase-3, caspase-9, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Additionally, curcumin exerts inhibitory effects on processes within the extracellular matrix (ECM), dampening the proliferation of leiomyoma cells. This action is facilitated through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) [99]. Notably, curcumin possesses robust antioxidant and anti-inflammatory properties, contributing to the maintenance of stable levels of fibronectin, collagen, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and vascular endothelial growth factor [88].
5.3 Vitamin D
Vitamin D acts as an anti-fibrotic agent, effectively diminishing the expression of key factors like proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 1 (CDK1), B-cell lymphoma 2 (BCL-2), and catechol-O-methyl transferase (COMT). This orchestrated suppression hinders cell proliferation and encourages programmed cell death within cultured human fibroid cells [100]. Total serum level of 1, 25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 was less in fibroids compared to myometrium of uterus in healthy women [112]. There is a dose-dependent response and an inverse correlation between the severity of uterine fibroids and serum vitamin D levels. So, vitamin D and their analogues can be used as a novel option for uterine fibroids treatment [113].
5.4 Berberine
A perennial herb Scutellaria barbata contains a plant-based alkaloid Berberine. Plants high in berberine lessen the effect of human chorionic gonadotrophin (HCG) on the proliferation of UF and myometrial cells [101]. Berberine blocks proliferation of uterine leiomyoma cells induced by oestrogen and progesterone as well as cell apoptosis, by keeping human normal uterine myometrium unaffected [114]. Uterine leiomyoma cells have cyclooxygenase-2 (COX2) and pituitary tumour transforming gene 1 protein (PTTG1) higher expression as compared to myometrium. It has been observed that berberine diminishes expression of both COX2 and PTTG1 [102]. There by indicates berberine as an antifibroid alkaloid.
5.5 Resveratrol
Red wines and several plant species contain resveratrol, a stilbenoid polyphenol. Resveratrol has strong anti-tumour and antioxidant properties [103]. Resveratrol inhibits ECM-related proteins like fibronectin, collagen types 1 and 3, fibromodulin, and biglycan expression. Additionally, resveratrol decreases expression of MMP-9 while increasing expression of tissue inhibitor of metalloproteinase 2 (TIMP2) protein in leiomyoma cells [115]. Resveratrol blocks the procreation of UF cells via the integrin v3 pathway. Pro-apoptotic gene p21 expression is increased by resveratrol, while anti-apoptotic gene expression is decreased. Resveratrol prevents Akt phosphorylation in uterine leiomyoma cells [104]. Resveratrol has an anti-proliferative and apoptotic effect on human cervical cancer cells by upregulating Bax expression, downregulating Bcl-2 proteins, and activating caspase-3 and -9 [105]. Resveratrol can be considered as therapeutic agent for leiomyoma.
5.6 Fucoidans
Highly sulphated polysaccharides known as fucoidans are present in a number of types of brown seaweed and brown algae. The type of carbohydrates, the amount of sulphates, and the molecular weight, all affect activity of fucoidans [106]. Although gamma-irradiated fucoidans exhibited stronger cell transformation inhibition, low molecular weight fucoidans possess to have greater cytotoxicity in cancer cell lines than natural fucoidan [107]. Fucoidans reduce the expression of fibronectin and connective tissue growth factor in fibrotic cells and also blocks TGF-1-induced epithelial-mesenchymal transition (EMT) [108]. In lungs, fucoidans blocks the ERK pathway to prevent the TGF-β1-related epithelial-mesenchymal transition [116]. According to a study, fucoidan induces cell growth reduction and lower the levels of the protein fibronectin, vimentin, α-SMA, and collagen. This organic compound reduced the translocation of β-catenin as well as the Smad2 and ERK1/2 pathways in this model [117] and has the potential of prevention of uterine leiomyoma.
5.7 Lycopene
Lycopene is a phytonutrient found in eatables including oranges, tomatoes, carrots, papaya, and watermelon that belong to the carotenoid family. The well-known antioxidant property of carotenoids shields cells from DNA damage, abnormal cell proliferation, and abnormal cell differentiation [109]. Incorporating lycopene into one’s diet has been associated with a reduced risk of gastrointestinal, prostate, breast, and lung cancer development [118]. Consuming β-carotene raises the risk of uterine fibroid, but only in women who smoke. Lycopene modulates anti-tumour immunity and has an anti-proliferative effect in part by altering the synthesis of cell cycle-regulating proteins [110]. Lycopene can be well tested as therapeutic compound for treatment of leiomyoma.
These natural therapeutic compounds have potential to suppress pathogenesis and growth of fibroid tumour by regulating cell signalling pathways, regulating cell proliferation and apoptosis such as TGF-β-WNT-catenin pathway, PI3K-Akt pathway and MAPK-ERK pathway. Curcumin and fucoidans specifically suppress TGF-β expression and berberine regulate WNT expression. These three suppress dysregulated TGF-β-WNT-catenin signalling pathway. Apart from these, EGCG, lycopene and resveratrol regulate ECM proteins formation such as fibronectin, collagen, globulin etc. and ECM excessive deposition. They also reduce irregular ECM intercellular skeletal changes, suppress initiation of basal node and resultantly stop tumour initiation. EGCG, curcumin and berberine also check excessive cellular proliferation and increased cell density, thereby reduce excessive fibroid growth. These natural compounds alter signalling pathways related to cell proliferation, transformation, as well as oxidative stress. Further by regulating many cyclin dependent kinases (CDKs), caspases these natural compounds alter cell cycle checkpoints and ceases more cell proliferation (Figure 2). Natural therapeutic compounds with anti-tumour properties are potential agents for uterine fibroid prevention and management. Understanding the role of natural products in pathogenesis of fibroid development will open a new window for clinician to treat uterine fibroid. It is quiet important to distinguish uterine leiomyomas with higher efficacy and developing more effective medical treatment to prevent necessity of hysterectomy, myomectomy, or UAE surgeries.
Uterine leiomyomas are benign monoclonal tumours that originate in the myometrium and can impact the endometrium negatively. They very rarely undergo malignant transformation. The formation of a leiomyoma entails the transition of normal smooth muscle cells into abnormal ones, followed by the growth and proliferation of these transformed myocytes, culminating in the development of a tumour. These leiomyomas are prevalent in approximately 80% of women of reproductive age. Common symptoms and indications of leiomyomas encompass irregular menstrual bleeding, pelvic pain, pelvic pressure, anaemia, infertility, and a tendency towards early pregnancy loss. Age, African-American race, obesity, less physical activity, malnutrition diet, alcohol and caffeine increase risk of fibroid development. Submucosal and intramural fibroids distort uterine cavity, affect implantation and leads to infertility. Alterations in genes such as MED12, HMGA2 and signalling pathways such as WNT-β-catenin stimulates uterine fibroid development. Oestrogen and progesterone along with their receptors are major mediators of fibroid growth. Due to their monoclonal origin, heterogeneity was observed in leiomyoma. Tumour within same uterus can be controlled by different genetic mechanism while two non-related patients can have same genetic defects.
Until today, major studies on fibroids concentrate on the involvement of steroid hormones in the formation of fibroid tumours. This results in development of medical treatment options like GnRH agonist, aromatase inhibitor and anti-progestins targeting theses steroid hormones. But no medical treatment was found that permanently shrink tumour or prevents its formation. Natural compounds such as EGCG, curcumin, vitamin D, lycopene, resveratrol have potential to alter signalling pathways related to cell proliferation, transformation, infection sensitivity, and oxidative stress. Regulation of cyclin dependent kinases (CDKs) and caspases alter cell cycle checkpoints and cease more cell proliferation (Figure 2). Efficacy and potential of natural compound as therapeutic agent is evident and a open window for future research in prevention and management of uterine leiomyoma.
Sonia Narwal has nothing to disclose. Minakshi Vashist has nothing to disclose. Rohit Kaushik has nothing to disclose. Vandana Kalra has nothing to disclose. Reetu Hooda has nothing to disclose. Sunita Singh has nothing to disclose.
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