| Pathophysiology of Fibroids |
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Introduction Uterine leiomyoma or fibroids as they are more commonly known, are the most common uterine growths found in women of reproductive age. The term ‘fibroids’ is a somewhat misleading as there is no fibrous tissue present. They are benign tumours comprised of smooth muscle. They are most usually found in the myometrium of the uterus although they are less commonly found in the cervix, broad ligament and rarely the ovary. A number of types exist, including some that present outside of the uterus. Some of the types are important to recognise as they can be mistaken for the malignant leiomyosarcoma (Robboy, Bentley, Butnor and Anderson, 2000, p779). Epidemiology It is estimated that uterine leiomyoma occur in around 20-30% of women over the age of 30 years of age and rising to over 40% in those over 40 years (Kjerrulf et al, 1996, p489). There are also definite racial differences. African women are more likely to suffer from fibroids and from a younger age than caucasian women. They also have more tumours present, suffer more pelvic pain and are more likely to be anaemic. However, these differences cannot be explained by a higher prevalence of risk factors (Kjerrulf et al, 1996, p4483-490). Women with fibroids have a lower parity and fewer term pregnancies than those without. It is recognised that infertility is a big factor in approximately 27% of women with leiomyoma, either as primary cause or a secondary one. However, it is not clear as to whether fibroids are a cause or a consequence of low family size, or both. Consequentially, the mechanism is likely to be mechanical distortion of the uterine cavity preventing implantation. Alterations in blood flow and an increase in the binding of hormones to the leiomyoma instead of the myometrium may also be a factor (West, 1997 p445). A study by Walker et al (2001, p 2049-2052) has made findings that suggest that the hormones associated with early pregnancy may have a protective effect against leiomyoma. Aetiology The aetiology of uterine leiomyomas is still indeterminate (Mackay, Beischer, Pepperell, Wood, 1990, p384; West, 1997, p444). There is a general consensus that their growth and maintenance is dependent on ovarian hormones such as oestrogen and progesterone (Mackay et al, 1990 p384; Woolf, 1998, p771, West, 1997 p445) as they are only really found during reproductive age. Other evidence to suggest that this is the case is that they also increase during pregnancy and shrink after menopause (Mcgee, Isaacson and Wright, 1992 p1607). Pathology Leiomyomas develop everywhere within the myometrium and occasionally in the cervix. The most frequent position is the wall of the myometrium and these are known as intramural fibroids. They can become very large or numerous and the uterus then becomes quite misshapen and the increased vascularity gives the appearance of pregnancy (Robboy et al, 2000 p780). Other locations for fibroid growth are the subserosal fibroids that project outward from the uterine surface but are covered by the peritoneum. These tumours are not restricted by the myometrium and so can grow to a very large size. They can also become pedunculated, especially if there is already an inflammatory disease present. These types have the capacity to cause peritonitis if they degenerate because subsequent infection can occur (West, 1997, p442). Submucous fibroids are less common and make up approximately 5% of all leiomyoma. They are relatively small and project into the uterine cavity, covered by the endometrium. They cause distortion of the uterus although the enlargement is not as evident as with intramural fibroids. Pedunculated submucous fibroids may eventually protrude through the cervix, causing bleeding or becoming infected. The expulsion of a submucous fibroid can even be mistaken for miscarriage as the tumour is mistaken for a foetal head. The different locations of fibroids are illustrated overleaf (taken from McCance and Heuter, 2002, p726). A number of different degenerative changes can take place with leiomyomas. The greater the size of the leiomyoma the more likely this will happen. The most common form is hyaline degeneration, where the smooth muscle cells are replaced by collagen and the tumour can become cystic if liquefaction occurs. The local blood vessels also undergo the same degeneration and calcification is secondary to the circulatory impairment that ensues. Necrobiosis, commonly know as ‘red degeneration’ usually occurs during pregnancy and can cause pain and fever. The fibroid eventually becomes white and calcified. Asides from the usual smooth muscle leiomyoma there are a number of less common forms of fibroids (Robboy et al, 2000, p781). The cellular leiomyoma is microscopically similar to the commoner leiomyoma but is much softer, this being a similar feature to leiomyosarcomas. This particular type of fibroid needs to be extensively checked, although the cellular leiomyoma does not have the mitotic activity or the coagulative cell necrosis typical of a leiomyosacrcoma. The haemorrhagic cellular leiomyoma is characterised by haemorrhage and cystic change and occurs in pregnancy and during oral contraceptive treatment. The combination of coagulative necrosis and raised mitotic rates makes this type a red herring for leiomyosarcoma. Symplastic leiomyoma is characerised by smooth muscle cells with multiple gigantic nuclei. This atypical appearance can also be a red herring for leiomyosarcoma. Diffuse leiomyomatosis of the uterus is a rare condition in which literally hundreds of small leiomyomatous nodules enlarge the uterus. They are quite frequently present with usual leiomyomas. Pathogenesis The pathogenesis of leiomyoma involves genetic alterations of the myometrium and interactions between oestrogen and progesterone with cytokines and growth factors that result in an immune response (Senturk et al, 2001, p559). Although there is much to explore in relation to these interactions, asides from the study of the role of oestrogens in the development of fibroids, there has been surprisingly little investigation into this area. There has been much research into the role of oestrogen and more recently progesterone in the development of fibroids and it has all served to strengthen the view that these ovarian sex hormones play a major role in the pathogenesis of fibroids (Tiltman, 1997, p48-51). Wilson, Yang and Rees, (1980, p20-24) demonstrated that the concentration of cytoplasmic oestrogen receptors in leiomyoma was significantly greater than of that in the myometrium. Ichimura et al (1998, p967-971) have found that upregulation of oestrogen and progesterone receptors does correlate with leiomyoma growth. Interleukin 8 (IL-8) is a cytokine that has been shown to stimulate cell proliferation in endometrial cells (Arici et al, 1998, cited in Stenurk et al, 2001, p564). Its production is induced by Tumour Necrosis Factor-a (TNF-a) and Interleukin-1 (IL-1) (Arici, 1993; cited in Senturk et al 2001, p559-566). The current treatment for fiborids, Gonadatrophin Releasing Hormone (GnRH) agonist, appears to decrease levels of IL-8 and its receptors either directly or indirectly by decreasing progesterone (Stenurk et al, 2001, p564). It is known that that progesterone increases the levels of IL-8 mRNA in human endometrial stromal cells (Arici et al 1996, cited in Stenurk et al, 2001, p564). Insulin like growth factor I (IGF-1) promotes cellular mitosis and differentiation and there is a strong presence of IGF-1 receptor sites in leiomyoma as compared to normal myometrium (Chandrasekhar et al, 1992, p64-69; Tommola, Pekonen and Rutanen, 1989, p658-662)). This suggests that there is a role for IGF-1 in leiomyoma growth. An in vitro study by Strawn et al (1995, p1837-1844) has concluded that IGF-1 preferentially stimulates leiomyoma cells with an autocrine and paracrine effect. It is interesting to note that IGF-1 gene expression is dependent on oestrogen, although IGF-1 receptor expression is not (Guidice, Irwin and Dsupin, 1993, p1796-1806). None-the-less, as IGF-1 promotes mitosis and differentiation, the necessity of oestrogen for these benign tumours has been partly explained. IGF-1 acts as a mediator for growth hormone (GH) and the incidence of uterine leiomyoma is increased in acromegaly (Danila-Muster et al, 1963, cited in Shahara and Nieman, 1995, p814-819). Although GH may exert its effect on the uterus indirectly by increasing IGF-1 secretion from the liver, the presence of GH receptors in human myometrium and leiomyoma suggests that GH exerts a more direct effect on the uterus (Shahara and Nieman, 1995, p814-819). Research has pointed towards disorders of prostaglandin synthesis and metabolism in menstrual disorders and this may also be true in the presence of fibroids (West, 1997, p445). Recently, Gonadatrohin releasing hormone agonists (GnRHa) have been used to treat fibroids. GnRHa causes both the leiomyoma and the uterus to decrease in size. However, The fibroids return to their original size when treatment is stopped. If the treatment is continued then the tumours still return to their original size after a year. GnRHa therapy has mostly been used prior to surgery, shrinking the tumours in order to keep complications such as haemorrhage to a minimum. GnRHa can also be used to help reduce menorrhagia prior to the menopause, although this is only a temporary measure. Management When considering the management of fibroids, it is important to remember that (a) they are frequently asymptomatic and symptomatic fibroids generally have either grown so large they need surgery or are degenerating, and (b) The complex pathophysiological interactions will be multidimensional and basically unknown for each individual. Oestrogen inhibiting herbs may be of some value to help slow down growth (Holmes, 1998, p944), and herbs to treat menorrhagia will also be useful (Hoffman, 1990, p100). However, The role for the herbalist really needs to take on a more holistic approach, especially as the aetiology for these tumours is unknown. It is becoming apparent that tumours may well be associated with emotional and psychological thought patterns ((Myss, 1997, p97;), although any considerations for holistic treatment needs to be done on an individual basis. Until recently the treatment of choice for problematic fibroids was either hysterectomy or for those who still wished to bear children - myomectomy. An increased chance of falling pregnant after myomectomy has also been observed (Smith and Uhlir, 1990, p 1476-9). Certainly when assessing the individual patient, the reproductive status should always be taken into consideration, as well as their symptoms and outlook. Conclusion The complexity of interaction amongst female sex hormones, cytokines and growth factors is so great, that unravelling the mysteries of fibroids will take some time. This is particularly because so little research is being done. This is not really surprising, given that uterine leiomyoma is a benign, frequently asymptomatic condition. However, the understanding of these interactions will still not answer the question of where did the oncogene that precipitated this vast array of interaction come from? What caused this genetic alteration in the first place? One can only conclude that the mind-body link predominates in this condition. Myss suggests (1997, p136) that the blocking of creative energy is a pattern that can give rise to disease within the reproductive organs. Other patterns are guilt and blame. |