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This assignment considers the development of uterine leiomyomata and their complications in relation to a case study. It deals with the pathophysiology, management and the psychosocial consequences of this disease. The case study is based on interviews, case notes and examinations.
Section A: Case History
ML is a 32 year-old Afro-Caribbean woman with a history of primary infertility and menorrhagia with severe dysmenorrhea.
Investigations for ML's menorrhagia began in 2003; an abdominal ultrasound scan found a 2mm intramural uterine leiomyoma in the body of her uterus, which was thought to be too small to cause ML's symptoms. However, ML began to develop lower back pain and polyuria and in 2010 the fibroid was shown to have grown to 4.7cm at its largest diameter. In 2012 it was decided to surgically remove the fibroid by myomectomy via laparotomy due to ML's worsening symptoms and persisting infertility. Pre-operative hysterosalpingography confirmed the mass, showing normal tubal patency and MRI revealed the fibroid had further grown to 6.3x5.4x7.1cm.
ML underwent menarche at age 11; her periods have always been heavy and irregular, occurring between 21-32 days and lasting for 4-7 days. They are often accompanied by rigors, vomiting, diarrhoea and sometimes ML falls unconscious from the intensity of the pain, which she describes at 9/10 on a verbal pain scale. Past history worth noting include a one-off result of mild dyskaryosis on a routine cervical smear test in 2012 which was followed-up by colposcopy and found to be normal. ML is currently not using contraception and takes co-codamol and tranexamic acid at the onset of her period, which she claims has little effect. ML and her husband had been attempting to conceive for seven years and in 2011 she underwent in vitro fertilisation which failed. She is allergic to NSAIDs and latex.
ML has a family history of uterine fibroids; both her mother and aunt having the disease. ML lives with her husband and works as a health care assistant. She has never smoked, doesn't consume alcohol and doesn't use illicit substances. Her husband is healthy and thought not to be a cause of the infertility problems. ML is recovering and mobilising well following her surgery.
Section B: Pathophysiology
Uterine leiomyomata (also known as fibroids and myomas) are benign monoclonal tumours. They arise from a single cell which originates from the myometrium smooth muscle layer of the uterus(1). Fibroids are supported with an abundance of extracellular matrix, fibronectin and proteoglycan, having a disordered arrangement of collagen(9). They vary in size and shape with a larger fibroids normally causing more severe symptoms(1). They have a variety of locations within and around the uterus (See Appendix B) of which intramural is the most common(1). Pedunculated fibroids must be monitored closely as they may tort upon themselves and become ischemic, whilst submucosal fibroids often cause the most pain(1).
Symptoms and Complications
As ML demonstrates, fibroids cause morbidity in multiple forms, yet they may be asymptomatic, especially when smaller. Menorrhagia is a common symptom with heavy, painful and deregulated uterine bleeds. The extent of bleeding can be measured by how many tampons/sanitary pads the patient uses and the possibility of anemia should be routinely monitored. The presence of the fibroid may cause dyspareunia and pelvic bloating, discomfort and pain throughout a menstrual cycle(1,3,9). Fibroids can distort the size of the uterus, compressing other viscera, which may cause back pain, constipation and urinary symptoms such as polyuria, dysuria and nocturia(1). ML's fertility problems were originally thought to be independent of her fibroids as this is a rare complication of the disease, yet recent evidence shows there may be a stronger association between fibroids and infertility than previously thought(1,5). Women with fibroids who do conceive are at increased risk of miscarriage and other complications of pregnancy such as premature labour and placental abruption(1). Fibroids are generally heterogenic to leiomyosarcomas; the two are thought to arise via a different mechanism(1,9), however, a rare subset of fibroids with mutations on chromosome one may lead to a malignant change(3).
Leiomyomata development follows a two-step progression; the first is the dysplastic change from normal myometrium to fibroid formation and the second involves growth and proliferation of these new cells(1,10,3). The multiple factors that act along this process of change will be discussed below (See Appendix C).
Genetics and Chromosomal Abnormalities
Fibroids have a strong genetic basis; over 40-50% of fibroids have significant cytogenic abnormalities which predispose to the disease(9,10). Chromosomal defects such as translocations between chromosomes 7, 12 and 14, deletions on chromosome 7 and trisomy of chromosome 12 are commonly found in fibroids(9). Fibroids are thought to be a polygenic disorder, commonly involving hereditary mutations in the FH, BHD and Tsc2 gene and somatic mutations in HMGA2 genes. These genes are important in myometrium cell regulation, proliferation, differentiation and growth(3); part of their action is to alter the myometrium's sensitivity to various hormones(10). Fibroids show an over-expression of oestrogen (α,β), progesterone (A,B), growth hormone and prolactin receptors(9,10). When hormones act on these receptors the cumulative effect is pro-mitotic with an increase in depositions of collagen and ECM(9,10).
Fibroids are hyperresponsive to sex-steroid hormones such as oestrogen and progesterone which aid in developing the fibroid. In addition to the myometrium overexpressing these hormonal receptors, there is evidence to support their levels being higher within fibroid itself(9) and factors that increase oestrogen such as low exercise, obesity and a nulliparous state have been shown to increase the incidence of fibroids.(3,9) It has been hypothesised that fibroids contain high amounts of aromatase which further increases oestrogen levels. The prevalence of fibroids correlates with this; fibroids are rare before puberty and post-menopausally, being most common in women of reproductive age. Progesterone also has growth effects; the greatest amount of mitotic activity occurs during the menstrual cycle secretory phase when progesterone is highest(8). Progesterone has been linked to upregulating several proteins important in cell growth, such as the bcl-2 protein, which has roles as an apoptosis inhibitor, suggesting progesterone has anti-apoptotic effects for fibroids(8).
Growth Factors and Angiogenesis
Paracrine and autocrine growth factors are over-expressed within fibroid tumour cells where they are thought to propagate the development of fibroids and to mediate the effects of sex hormones(8,9). They have been shown to promote fibroid mitogenesis, angiogenesis and reduce inhibitory factors of growth such as metalloproteases (See Appendix D for a breakdown of how the different growth factors act). Some growth factors, especially vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGFP), have vasoactive properties and increase vascular permeability, resulting in a change in coagulation pathways(10). The aetiology of menorrhagia is uncertain, but could be due to the roles of these angiogenic growth factors causing excessive bleeds or venous compression, resulting in ectasia(9).
The risk factors for leiomyomata should be considered cautiously as the evidence often has confounding factors which may lead to misinterpretation of the data, such as increased monitoring of symptomatic women, limitations of the studied population and high background prevalence which may be understudied(9,8,1).
Increased oestrogen exposure is a major determinant in fibroids, exacerbated by factors such as early menarche and late menopause(3,9), yet conversely oestrogen-hormone replacement therapy and the oral contraceptive pill are unlikely to affect the disease(9). Increased body-mass index (BMI) is a risk factor as adipose contains aromatase and has roles in inhibiting sex-hormone binding globulin (SHBG) synthesis, thus increasing the amount of unbound oestrogen in the blood(9).
ML has several other risk factors, including family history; having a first-degree relative with fibroids increases risk by 2.5x. ML's ethnicity has implications as Afro-Americans are 3x more likely to have the disease than Caucasians; the aetiology of this is uncertain but may be due to genetic components, specifically mutations concerning COMT, an enzyme which has a role in degrading oestrogen(9).
The role of diet and lifestyle is uncertain, but studies have been found showing a high intake of red meat is harmful, while green vegetables and smoking are protective(1).
Pregnancy is protective for fibroids, yet has little or no effect on established fibroid size(3). Fibroids exhibit a similar phenotype to a 'pregnant' myometrium, with increased extra-cellular matrix and hormone receptor expression, yet are unable to regress like normal myometrium, possibly due to a lack of autocrine cyclo-oxygenase-2(3). In women with fibroids who then become pregnant, the high quantities of such enzymes may enable the fibroid to regress in the later stages of pregnancy(3).
Section C: Diagnosis and Treatment
When a history highlights the possibility of fibroids, a pelvic examination will be performed; palpation may show an irregularly shaped, non-tender uterus whilst bimanual examination gives a good indication of uterine size(1,9). Diagnosis can often be made using history and examination alone, yet these techniques are only adequately sensitive for subserosal or intramural fibroids(9).
Imaging for fibroids can be performed in several modalities, used to detect size, number and position of fibroids(9). Abdominal or transvaginal ultrasound is often used to confirm the diagnosis and exclude other conditions, such as ovarian or uterine neoplasm(1,9). Hysteroscopy and more rarely laparoscopy may also be used, whilst MRI is the best modality for deep and submucosal fibroid(9). A biopsy may be taken during these investigations for exclusion of other conditions(9).
Medical Treatment for Menorrhagia and Fibroids
ML was informed and included about the decisions for her treatment; patients should have treatment for fibroids that takes into consideration their age, symptoms and desire for future fertility(12,13). Only symptomatic fibroids are considered for treatment.
ML was taking tranexamic acid at the onset of menses, yet found it had little effect on her symptoms and she experiences the common side effects of nausea and leg cramps(13). Tranexamic acid is an antifibrinolytic that acts as a reversible antagonist of plasminogen; it has been shown to reduce blood loss during menstruation by 40%(13).
Mild steroids with androgenic effects such as Danazol and Gestrinone have anti-oestrogenic and anti-progesterone effects, resulting in a reduction of uterine size, fibroid size and menorrhagia(12), therefore also improving anemia(1). 20% of patients using these treatments experience amenorrhoea and 70% oligomenorrhoea(12,13). There is a high incidence of androgenic side effects, such as acne, seborrhoea, myalgia, arthralgia and weight gain(12).
Gonadotrophic-Releasing Hormone (GnRH) Agonists
GnRH agonists such as Buserelin and Goserelin are administered intra-nasally, subcutaneously or intramuscularly in a regular fashion. They cause a down-regulation of GnRH-receptors on the pituitary gland, which induces a hypogonadotropic hypogonadal state after 1-3 weeks due to a reduction in FH and LSH (12). They may reduce the fibroid size by 51-61% and improve anemia and menstrual symptoms(12). However, GnRH agonists have menopausal side effects of amenorrhoea, hot flushes, vaginal dryness, headaches, bone loss and can cause depression, meaning they cannot be given indefinitely(12). When GnRH agonists are removed, the fibroid rapidly undergoes regrowth(12).
As in the case of the above, many of the medical treatments for menorrhagia will induce a state of oligomenorrhoea or amenorrhoea meaning they are contraindicated in patients like ML who are trying to conceive(12,13). However, these therapies should be considered in patients who have already completed their family(13). As these treatments were contraindicated in ML I shall not discuss them further, yet please see Appendix E for further details.
After the decision was made to surgically remove or reduce the size of the fibroid, ML was offered three surgical options: hysterectomy, uterine artery embolization (UAE) and myomectomy. Other surgical options exist, but shall not be discussed here.
Hysterectomy is the removal of the uterus and acts to permanently resolve problems with fibroids for patients who have already completed their family and when all other causes of symptoms have been excluded(5). Hysterectomy may be performed open or laparoscopically and GnRH agonists may be given in the weeks pre-operatively in an attempt to reduce fibroid size(5). Whilst hysterectomy has high satisfaction rates, it is the most expensive form of surgical management, with the longest post-operative hospital stay(1,5).
Uterine Artery Embolization (UAE)
UAE involves the occlusion of one of the major sources of myometrium vasculature, the uterine artery(2). The procedure can be performed under local anaesthetic and the uterine artery is accessed via the femoral artery in the thigh(5). Beneficial effects include a reported 90% reduction in menstrual symptoms(5) and a reduction in uterine volume(1). It is performed for patients whose primary complaint is menorrhagia and anemia and who have completed their family as 5% of patients experience amenorrhoea(1,2). UAE has the fastest recovery of surgical interventions for fibroids and thus has a shorter post-operative hospital stay and a faster return to work(2,22). However, complications include infection in 1-18% of patients, a self-limiting post-embolization pain, leukocytosis, and pyrexia(5). There is also a risk of treatment failure and recurrence of fibroids(2).
ML decided to undergo a myomectomy procedure as it is indicated for women who wish to preserve fertility and have future children(1). A myomectomy involves the removal of the fibroid whilst conserving the uterus and can be performed via laparotomy, laparoscopically or hysteroscopically(1). As in the case of hysterectomy, a GnRH agonist may be given pre-operatively to reduce the fibroid size(5). Myomectomy in general relieves fibroid-related symptoms and improves fertility, although there is a high risk of recurrence, with some studies suggesting 50% of patients will go on to develop new fibroids within five years(1).
The decision as to which route a myomectomy is performed is determined by a multitude of factors, yet the speciality and preference of the surgeon involved play a major part(1). Laparoscopic myomectomy is performed in woman who have a uterine size of 16 weeks pregnancy or less, indicated for fibroids that are subserosal or intramural, where the procedure is thought to be uncomplicated(1). C. Jin et al. meta-analysis shows that laparoscopic myomectomy has less operative blood-loss, faster recovery and less post-operative pain than laparotomy, whilst also reducing infection risk(11). Hysteroscopic myomectomy is indicated when the fibroids are submucosal and few in number, making them uncomplicated to identify and remove(1). This can be performed as day-surgery, under local anaesthetic, showing multiple benefits for both the patient as an individual and for the total cost of the operation(1).
Section D: Psychosocial Aspects
Uterine fibroids are the benign tumour most commonly found in the female genital tract(10): studies show the lifetime risk may be as high as 70%. The exact prevalence of uterine fibroids is difficult to obtain; the disease is clinically apparent in 25-33% of woman(1,10), yet novel imaging modalities may show the clinical prevalence is higher(1). Pathological examination and histological studies show that the true prevalence may be in the range of 60-77% of females(1,10). The disease is more prevalent in Afro-Caribbean populations with Afro-Caribbean women being more likely to have an earlier age of diagnosis, faster disease progression and longer-lasting symptoms post-menopause(1). Due to the influence hormones have on the disease age has a significant effect; fibroids are most commonly diagnosed in women over 45 and rarely diagnosed in adolescents(1). Post-menopause, as oestrogen levels fall, fibroids commonly regress(8) and new fibroids are generally significantly smaller than when found in women of reproductive age(9). Specimens obtained from women who underwent hysterectomy for fibroids show premenopausal women have a greater number of fibroids than postmenopausal women, with an average number of 7.6 and 4.2 respectively(9).
The high clinical prevalence and the subsequent health consequences mean that uterine fibroids have a large economic cost and seriously impair patient's quality of life(1). Whilst surgical treatment of fibroids is the most expensive factor in this disease, the management of symptoms, imaging costs and health professional's time should all be considered(16). Hysterectomy and myomectomy are the most expensive forms of surgery, whilst in contrast, UAE is more cost-effective and has a reduced post-operative hospital stay(2,16). The more invasive forms of surgery can have an recovery period of up to six weeks and the time away from work has implications for both society and the individual(15).
Fibroids can often be found incidentally, and the patient should be informed of this. Whilst fibroids are prevalent, they are a disease less understood in the general population and a misunderstanding of the disease may cause fear and anxiety(19). Patients with asymptomatic fibroids are concerned about the possibility of malignancy, compromised fertility or pregnancy, future growth of the fibroid and whether a hysterectomy will be necessary(19).Clinicians should carefully explain the implications of this diagnosis.
Menorrhagia can severely impact upon a woman's quality of life; the condition itself can be embarrassing as can be the associated attributes, such as regularly using the toilet to change tampons or sanitary pads(21). This may impact upon a woman's relationships and work causing feelings of anxiety and discomfort(21). Severe menorrhagia may cause anemia, fatigue and pain leading to a prolonged disruption to everyday life(21).
After fertility-preserving treatment, women generally express an improvement in sexuality and psychological well-being(18). The reduction in physical symptoms of menorrhagia, fatigue, anemia and possibly the restoration of fertility comes as a relief to patients, many of whom have suffered chronically(18). Patients may experience an improvement in body image improving sexuality and psyche, which positively reinforce each other(18). However if complications of UAE develop, such as infertility or pregnancy, patients are at high risk of developing anxiety and depression(20).
Hysterectomy causes a many patients to experience the psychological improvements listed above(17). However, the removal of a patient's uterus may cause a distortion of their body image and perceived loss of womanhood, which can lead to a negative change in affect(17). The 'surgical menopause' effects of hysterectomy, such as vaginal dryness and loss of libido can severely impact upon patient's sexuality and quality of life(17).
As shown, uterine fibroids and their complications are important conditions that seriously impair patient's quality of life. Treatment should be tailored to an individual patient's needs, with patient preference being the primary indication for which modality to use.