Clinical Review: Uterine fibroids

Fibroids are the most common tumours among the female population.

Uterine fibroids: incidence increases with increasing age
Uterine fibroids: incidence increases with increasing age

Section 1: Epidemiology and aetiology
The incidence of uterine fibroids increases in women with increasing age, affecting more than 30% of women aged 40 to 60 years.

The exact aetiology of uterine fibroids is not completely understood. There is evidence that fibroids are monoclonal tumours that grow from a single mutated uterine smooth muscle cell at various sites within myometrium. However, the initiating and promoting factors influencing growth of these single myometrial cells is not clearly understood.

Estrogen and progesterone hormones, along with other growth factors, have been shown to have direct influence.

Environmental factors
Environmental factors have also been shown to influence fibroid formation. Smoking appears to decrease the risk of fibroid formation and growth. This is thought to be secondary to reduction in circulating SHBG, which is a direct result of the effect of smoking on liver enzymes. This leads to a rise in the level of free estrogen, which has a mitogenic effect on fibroids.

Body weight and eating habits influence the risk of developing uterine fibroids. Uterine fibroids are two to three times more common in obese women. There is also evidence to suggest that excessive dietary intake of beef and ham is associated with increased risk of developing fibroids. In contrast, a diet rich in green vegetables decreases the risk. A number of animal studies have also shown an inhibitory effect of green tea extracts on uterine fibroids.

Despite these findings, there is no evidence that dietary changes, following presentation and diagnosis of uterine fibroids, would have any influence on a patient's symptoms.1

Genetic factors
Genetic and hereditary causes are being considered and several epidemiological findings indicate considerable genetic influence, especially for early onset cases. Chromosomal abnormalities are present in nearly 50% of fibroids and mutations in the MED12 gene have been documented in 70% of fibroids. However, it is interesting that when multiple fibroids are present, unrelated genetic defects can be detected, adding to the complexity of genetic predisposition. Nevertheless, it is well established that first-degree relatives have a 2.5-fold increased risk and this can be a nearly sixfold increased risk in early onset cases.

In addition, clear differences in disease prevalence in different racial groups, in particular in women of African origin, further highlight an underlying poorly understood genetic predisposition to the condition.

Section 2: Making the diagnosis
Fibroids are round, well circumscribed, solid nodules with variable size, from microscopic to huge masses filling the whole abdominal cavity (see main image above). Generally, fibroids the size of a grapefruit or bigger can be felt by the patient and are readily noted on bimanual pelvic palpation.

Fibroids are often asymptomatic. However, larger fibroids could cause many symptoms, depending on their size and location.


MRI scan: particularly useful in establishing position of fibroids (Photograph: SPL)

Key symptoms
Important symptoms include heavy or painful periods, abdominal discomfort and bloating, backache, painful defecation, urinary frequency or retention.

In some patients, fibroids can result in dyspareunia or infertility, depending on their position. Submucous fibroids are thought to interfere with the implantation process and larger fibroids can block the fallopian tubes.

During pregnancy, fibroids may be the cause of miscarriage, premature labour, pain or malpresentation of the fetus. Cervical and lower uterine fibroids can also interfere with labour and make caesarean section delivery challenging. Rarely, fibroids are located in the round ligament, broad ligament, or uterosacral ligament of the uterus, making differential diagnosis from an ovarian lesion difficult.

Imaging modalities
The diagnosis of fibroids is primarily based on imaging, either ultrasound or MRI. In both modalities, fibroids have characteristic features that are easy to diagnose. However, secondary changes can sometimes develop in fibroids (haemorrhage, necrosis, calcification or cystic changes) that can make diagnosis difficult, in particular on ultrasound scan.

Transvaginal ultrasound scan (TVS) is more reliable than abdominal ultrasound in assessing uterine fibroids, especially in obese patients. The readily accessible and cost-effective aspect of TVS has made it the preferred first-line investigation in patients with suspected uterine fibroids.

MRI is a costly but powerful investigatory tool that is particularly useful in establishing the exact position, characteristics and number of fibroids, and their associated relationship with the adjacent viscera.

MRI is especially useful in patients with large fibroids or pedunculated fibroids that can be disguised as an adnexal mass. In addition, in patients with large fibroids, the ovaries are lifted out of the pelvis and may not be readily identifiable with ultrasound. This is easily overcome with MRI.

As yet, there are no imaging modalities that can distinguish benign uterine fibroids from malignant uterine leiomyosarcoma. Fast growth, in particular after menopause, may raise the index of suspicion that the lesion might be a sarcoma.

However, such observation, although it appears intuitively reliable, is not supported by the available data in the literature, partly due to the rarity of leiomyosarcoma.2

Section 3: Managing the condition
Medical treatment

A number of medications are used to treat the symptoms of fibroids, including NSAIDs for pain, oral contraceptives to reduce uterine bleeding and iron supplements for anaemia.

The levonorgestrel intrauterine system (IUS) effectively reduces menstrual blood flow, even in patients with fibroids; there is evidence to suggest it may induce a degree of regression. However, spontaneous expulsion is more frequent in patients with fibroids.

Danazol provides effective symptomatic relief and reduces fibroid size, but is rarely used because of side-effects.

Gonadotropin-releasing hormone (GnRH) analogues can cause regression by decreasing circulating estrogen. Owing to their side-effects and the risk of osteoporosis, they are often used temporarily, before surgery, to shrink fibroids. GnRH analogues can be considered in conjunction with add-back HRT to alleviate side-effects.

Growing evidence suggests progesterone plays a key part in fibroid development and growth. Progesterone antagonists such as mifepristone have been shown to reduce the size of uterine fibroids, but significant side-effects have been noted.

Research is focused on a selective progesterone receptor modulator (asoprisnil), which it is hoped will be as effective as progesterone antagonists but without major side-effects.3


Endoscopic view showing surgical removal of fibroids (Photograph: SPL)

Uterine artery embolisation
Uterine artery embolisation (UAE) is a safe, effective and well-established radiological technique used in the management of symptomatic fibroids as an alternative to myomectomy. It is advocated in women who have completed their family.

UAE can significantly alleviate pain, menstrual loss and pressure effects from fibroids. The average decrease in fibroid volume is about 40%, although some report up to 70%.

This is similar to what is often achieved with GnRH agonists, except that the fibroid does not regrow after cessation of treatment. Furthermore, shrinkage tends to continue many months after UAE; with GnRH agonists it is limited to the first three to six months.

Complications with UAE are generally uncommon, but include adverse reactions to the contrast media, haematoma, thrombosis or pseudo-aneurysm. Vaginal discharge and abdominal pain are common following the procedure but usually resolve in a few days. The vaginal discharge can become chronic and foul-smelling, due to fibroid expulsion, and surgical evacuation of the uterus may be required.

Post-embolisation syndrome may occur in a small number of patients. Patients present with pain, flu-like illness, mild pyrexia and nausea in association with raised inflammatory markers. If these symptoms persist, infection must be suspected and promptly treated.4

Despite good shortand medium-term outcomes, a significant number of women will require hysterectomy or repeat embolisation. The HOPEFUL trial showed that 23% of women required further intervention following UAE at a mean follow-up of 4.6 years.5

There is also an association between UAE and ovarian failure, hence it is contraindicated in patients who wish to become pregnant. In addition, there is evidence to suggest that UAE is associated with spontaneous abortion, abnormal placentation, preterm delivery and postpartum haemorrhage. It appears these complications are more common after UAE than after myomectomy.5

There are a few reported case series from advanced laparoscopic surgery centres on uterine artery occlusion in the management of fibroid- related symptoms. The principle is similar to UAE but occludes uterine arteries externally using clips, ligatures or diathermy.

Short-term follow-up data on this technique are promising but the need for general anaesthesia and surgical intervention make it more applicable to centres with no access to UAE expertise or resources.

High-intensity focused ultrasound
High-intensity focused ultrasound is a non-invasive thermo-ablative technique that focuses ultrasound waves on fibroid tissue, raising the temperature within the diseased tissue and destroying it. The procedure has been enhanced by the use of MRI to guide it (MR-guided focused ultrasound).

Data on this new technique are promising, although the reduction in size of fibroids seems modest compared with other modalities and importantly, only a small number of fibroids can be treated per session. Hence, patients with multiple fibroids are either unsuitable or need multiple treatments.6

Myomectomy
Myomectomy is usually recommended in patients who wish to preserve their fertility and have not responded to medical treatment. It can also be considered in a patient who strongly wishes to retain her uterus.

This is most often done by laparotomy, but increasingly via laparoscopy or hysteroscopic resection. There is a small associated risk of hysterectomy, most often due to excessive intraoperative bleeding. Myomectomy is also associated with a risk of postoperative adhesion formation and recurrence.

Hysterectomy
Hysterectomy remains a common option in patients with fibroids who have completed their family and failed to respond to medical management.

Endometrial ablation
Endometrial ablation can be considered in selected patients with no fertility concerns. It is suitable for those primarily with menstrual bleeding problems. The extent of endometrial cavity distortion is important in the selection of suitable patients.

Section 4: Prognosis
Fibroids are dependent on estrogen and progesterone to grow and they tend to shrink after menopause.

There have therefore been concerns about whether HRT should be prescribed, particularly in perimenopausal patients who are experiencing heavy menstrual bleeding.

Prescribing HRT
Very few studies have examined the question of prescribing HRT. It appears that generally, the increase in fibroid size is not significant and should not have a major influence on symptoms.

However, the best course of action is to monitor the size of the fibroids and the patient's symptoms following the introduction of HRT. Tibolone, a synthetic steroid with weak estrogenic effects, may be considered as an alternative.

Malignancy
The malignant version of a fibroid is extremely uncommon and is termed a leiomyosarcoma. The incidence of malignant transformation of fibroids is difficult to determine because many women have asymptomatic fibroids and are unaware of their presence.

However, the incidence of uterine leiomyosarcoma is low, in particular in young patients in their reproductive years.7

Section 5: Case study
A 42-year-old nulliparous patient of African descent was admitted to the intensive care unit with septicaemia following multiple dental extractions. She was found to be in renal failure, with a grossly distended abdomen due to a large 36-week size solid mass.

CT images revealed a large uterine mass with associated bilateral hydronephrosis and an atrophic, non-functioning left kidney, probably due to severe hydronephrosis on that side.

In addition, a thrombus was noted within her left common iliac vein as the result of compression by the uterine mass. She reported no menstrual problems and no bowel or urinary symptoms. However, she had noted worsening abdominal distension over the preceding 18 months.

Further MRI suggested very large uterine fibroids with heterogeneous features compressing adjacent viscera. The possibility of leiosarcomatous changes was therefore raised.

Further review
Her images were reviewed in the regional cancer meeting and the suggestions confirmed by the lead cancer radiologist. UAE was ruled out due to pelvic vein thrombosis and raised suspicion of malignancy. Her sepsis resolved and she was transferred to the cancer unit for hysterectomy, following insertion of an inferior vena cava filter.

The patient underwent major laparotomy; the fibroids proved to be bilateral giant ovarian fibromas, with no evidence of malignancy on histological assessment. Her uterus appeared to contain a few small fibroids and was preserved.

The differential diagnosis of ovarian fibroma and uterine fibroids, in particular pedunculated fibroids, can be exceedingly difficult on imaging.

CA125 is of limited value; it would be moderately elevated in both cases. However, absence of menstrual symptoms or highly elevated CA125 could be more suggestive of ovarian pathology.

Section 6: Evidence base
Clinical trials

The largest observational study comparing the results of UAE carried out in large units throughout the UK and hysterectomy.

According to these researchers, UAE appears to be at least as safe as surgical treatment and the associated complication rates compare favourably with those for hysterectomy.

  • Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results. BJOG 2011; 118: 936-44.

This trial demonstrates no significant differences between the two treatment modalities.

Symptom score reduction and patient satisfaction with either treatment were very high. Rates of adverse events were also similar in both groups.

However, the five-year intervention rate for treatment failure or complications was 32% for UAE and only 4% in the surgical arm.

Guidelines

Key texts

A comprehensive review covering the epidemiology, aetiology, pathogenesis and management of uterine fibroids.

A well-written review article on the management of uterine fibroids, with particular emphasis on the role of UAE in their management.

Curriculum
This topic falls under section 10.1 of the RCGP curriculum, Women's Health.

Reflect on this article and add notes to your CPD Organiser on MIMS Learning

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • At a clinical meeting, revise the causes of abdominal pain in women, including during pregnancy.
  • Create a practice protocol on the management of fibroids.
  • Audit your gynaecology referrals over the past six months; could you have managed these patients differently?

Contributed by Mr Farhad Alexander-Sefre, consultant gynaecological surgeon at the Glasgow Royal Infirmary.

References
1. Stewart EA. Uterine fibroids. Lancet 2001; 357: 293-8.

2. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007; 87(4): 725-36.

3. Wilkens J, Chwalisz K, Han C et al. Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy. J Clin Endocrinol Metab 2008; 93: 4664-71.

4. Lumsden MA. Embolization versus myomectomy versus hysterectomy: which is best, when? Hum Reprod 2002; 17: 253-9.

5. Dutton S, Hirst A, McPherson K et al. A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy. BJOG 2007; 114: 1340-51.

6. Zaher S, Gedroyc WM, Regan L. Patient suitability for magnetic resonance guided focused ultrasound surgery of uterine fibroids. Eur J Obstet Gynecol Reprod Biol 2009; 143(2): 98-102.

7. Amant F, Coosemans A, Debiec-Rychter M et al. Clinical management of uterine sarcomas. Lancet Oncol 2009; 10: 1188-98.

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