The Incidence, Aetiology And Treatment of Leiomyoma in Nigeria
Summary
Leiomyoma are a significant source of morbidity in reproductive aged woman across the globe causing distressing symptoms and in infertility in some women. There does, however, appear to be an increased incidence of leiomyoma in women of black African ethnicity and especially those women in Nigeria. This review covers the incidence and possibly aetiology and treatment of leiomyoma in Nigeria.
Keywords: Nigeria; Uterine leiomyoma; Genetics; Aetiology; Treatment; Interventions
Introduction
Uterine leiomyoma, commonly known as uterine fibroids, is a benign tumor often found in women of all races across the world. There is a 3-4-fold likelihood of dominance among African women as opposed to what is seen in other races [1-4]. Leiomyoma occurs mostly in women of reproductive age and have been observed by some workers in 80% of women in Nigeria within the age range of 25 years and above. Leiomyoma generally begins with a small mass which further grows into a larger mass. There is generally a late presentation of patients at clinics as most leiomyoma is asymptomatic [5,6]. A study by Baird DD, et al. [7] showed a 60% incidence of leiomyoma among African American women at age 34 with a surge of greater than 80% when they attain age 50. This is in contrast to as what was observed in Caucasians who have 40% incidence at age 35 and 70% at 50.
The Aetiology of Leiomyoma
The aetiology of leiomyoma is currently unknown but many predisposing factors have been proposed such as age, race, nulliparity, early menarche, caffeine and alcohol consumption, positive family history, vitamin D deficiency, hormonal factors, the use of chemical hair products, obesity and genetic factors [8- 10]. The development of leiomyoma is thought to depend upon the female hormones oestrogen and progesterone. Studies have established the presence of oestrogen and progesterone receptors on the surface of leiomyoma along with higher mRNA and protein expression level when compared with the normal myometrium [11-13]. Varying degrees of symptoms have been observed in patients suffering from leiomyoma depending on the size and location of the leiomoyma [14]. The most common symptoms are menorrhagia with secondary anaemia, infertility, pregnancy loss, obstetric complications and pelvic pain [14]. In this review we focus on the genetic predisposition to leiomyoma, the current available therapeutic interventions and the potential of stem cells in the prevention of leiomyoma and optimization of the uterine endometrial environment.
The Genetic Basis of Leiomyoma
The pathogenesis of leiomyoma is not fully understood. Nevertheless, some insights have been documented such as the observation of Mehine M, et al [15] who linked leiomyoma with complex multiple chromosomal rearrangements due to multiple chromosomal breaks and random reassembly. These chromosomal rearrangement result in tissue specific changes observed in leiomyoma which could be explained by the translocation of (High mobility group) HMGA 2 and RAD51B loci and mutation at the COLAA5- COLAA6 HMGA2 gene found in translocation 12:14 which has three DNA binding domains. These domains are responsible for the attachment of its protein to adenine-thymine (AT)-rich regions of DNA. This binding neither promotes nor inhibits the transcription process during myometrial stem cell division but alters the DNA structure to encourage complex formation of transcription regulatory proteins [16]. This single genetic mutation may alter key the signaling pathways such as those involving β-catenin and TGF- β. These are major cell proliferation regulators resulting in the inability of the cell to control its survival and senescence [17].
Other chromosomal changes have been directly linked to the pathophysiology of leiomyoma among which includes the observation that 40% of leiomyoma patients have tumor specific chromosomal mutations [18,19]. In familial leiomyoma transferable germline mutations have been observed to result in fumarate deficiency and a gene that could predispose women to leiomyoma has been mapped on chromosome 1q42.3-q43 [20-22]. Despite these observations it is not currently understood how fumarate deficiency promotes the growth of leiomyoma. One possible hypothesis is that mutation in fumarate hydratase in the citric acid cycle could result in leiomyoma development through the citric acid mediated mitochondrial dysfunction causing DNA damage, loss of energy dependent apoptotic function and inhibition of growth factor transcription [23]. In a study conducted by Mäkinen, et al. [24] 18 leimyoma tissues and normal myometrium tissues were subjected to sequencing after which it was shown that 56% of the leiomyoma tissue (10 of 18) had a mutation in the gene that codes for the mediator complex subunit 12 (MED 12). The MED12 gene (Xq13.1) provides instructions to make a protein, mediator complex subunit 12, which regulates transcription through RNA polymerase II by linking transcription factors which influence whether genes are turned off or on [24]. Mis-sense and in-frame insertion-deletion mutations in the MED12 gene have been confirmed to contribute to the pathogenesis of leiomyoma. The MED12 mutation has been reported to be the most common form of mutation in leiomyomas contributing to about 70% of all cases [25].
In normal stem cells, the MED12 gene acts as a physiological modifier of β-catenin; however, when a mutation occurs, this function of the MED12 gene is lost. Moreover, TGF-β receptors are expressed in stem cells, which activate mitogenic protein kinase (MAPK) proteins, which regulate cell-cell interactions, renewal, and proliferation of stem cells [26].
In reproductive age women, myometrial smooth-muscle cells undergo cell division and involution under the influence of ovarian hormones or the hormones of pregnancy. A point mutation in MED12 resulting in a chromosomal rearrangement could also result into increased expression of HMGA2, or some other gene defect in a somatic stem cell in the myometrium, may be the initiating factor [27].
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