Pathophysiology

Uterine fibroids (uterine leiomyomas) are a common, benign tumour thought to affect as many as 77% of women of reproductive age, although only 25% of Caucasian women are symptomatic.  The aetiology of fibroids has not yet been reliably described although a number of factors are thought to contribute to their development, including genetic mutations and ethnicity (9 times higher rate in Afro-Caribbean women). 

In addition a major risk factor that has been identified is exposure to unnopposed oestrogens. Causes of increased oestrogen exposure include:

  • Obesity
  • Early Menarche
  • Late menopause
  • Nulliparity
  • Use of synthetic oestrogens such as Tamoxifen in treatment for CA breast

 

Interestingly it has been suggested that smoking tobacco has a protective effect on the development of uterine fibroids.

 

Causative factors for fibroids

Research has shown that uterine fibroids are monoclonal in origin, i.e. they stem from a single mutated myocyte.  Initiation and promotion of this single myometrial smooth muscle cell is poorly understood.  Chromosomal abnormalities have been described in approximately 40% of cases, however the fact that 60% of these tumours display a ‘normal’ karyotype implies external influences (such as those shown in figure 1) have an important role,  in addition to any genetic factors.  Chromosomal anomalies that have been identified are varied and include trisomies, deletions, translocations and rearrangement.

There are also some hereditary genetic abnormalities that predispose to uterine fibroids, including defects with FH, BHD, TSC2 and HMG2A which may explain why women who have a first degree relative with uterine fibroids are 2.5 times more likely to develop one themselves.  The fact these tumours are monoclonal in origin, means each lesion is discreet.  In a uterus with multiple fibroids, several distinct genetic disruptions may be present, or indeed genetic abnormality may be present in some, but not all lesions. 

Presentation and Diagnosis

Although benign, and the majority (50%) asymptomatic, the presence of a clinically significant uterine leiomyoma has the potential to cause a considerable level of morbidity.  There are three recognised presentations of symptomatic uterine leiomyomas which may occur in connection with one another or in isolation:

  • - Abnormal bleeding per vaginam (30%)
  • - Pain and/or pressure effects in the pelvic area e.g. urinary frequency or torsion of pedunculated lesions leading to pain (rare)
  • - Reproductive dysfunction e.g. submucosal fibroids preventing implantation

 

Fibroids may present with their complications, rather than as the presenting complaint.  Known complications of fibroids include:

  • - Red degeneration - inadequate blood supply to the centre of the lesion leading to a necrotic core with associated pain.  This is especially common in pregnancy.  
  • - Post partum haemorrhage due to inefficient uterine contraction
  • - Abnormal lie of a foetus if the fibroid is located inferiorly
  • - Mailignancy - 0.1% progress to leiomyosarcomas.
  • - Mesenteric vein thrombosis and thromboembolism
  • - Urinary retention, leading to renal failure
  • - Intestinal gangrene
  • - Acute haemorrhage

 

Leiomyomas can develop anywhere in the human uterus, and their location can greatly influence the symptoms experienced; large anterior or posterior masses are those most likely to cause urinary dysfunction or constipation respectively.  Location also influences the bleeding pattern experienced, with sub mucosal lesions causing a disproportionately high level of bleeding.  Lesions are not always easily classified as 'subserosal' or 'intramural' for example; they may be mixed, such as is demonstrated by 'A' and 'C' on the diagram below.  

 

The diagnosis of uterine leiomyoma is usually suspected following a suggestive history, and an irregular uterine contour on pelvic or abdominal examination. If the diagnosis is unclear at this stage MRI or ultrasound scanning can be used.  They may also be discovered incidentally i.e. during hysteroscopy for an unrelated indication.  

Depending on the presenting complaint, other pathology such as ovarian or endometrial disease should be excluded as an asymptomatic uterine leiomyoma may mask more sinister pathology. 

Possible locations of uterine fibroids.  With kind permission from the University of North Carolina

Management

Uterine fibroids display a spectrum of clinical characteristics from asymptomatic small lesions that are discovered incidentally, to troublesome symptoms that have the potential to be life-threatening. Treatment options are guided by the clinical findings, and the reproductive wishes of the patient.

 

1. Conservative management:  Asymptomatic lesions can be managed expectantly which has many advantages; the risks of surgical intervention are avoided and a substantial amount of money is saved.  Conservative management consists of regular ultrasonographic monitoring and gynaecological review. As uterine fibroids are oestrogen dependent, there is a marked improvement upon initiation of the menopause and so women who are approaching the menopause may chose a trial of expectant management if their symptoms are not too bothersome.

 

2. Medical Management: The main aims of medical therapy are to prevent excessive blood loss and the subsequent anaemia, and to reduce uterine size and thus any pressure effects the uterine mass exerts. There are several treatments in use that do one or both of these things:

  • Tranexamic acid, NSAID's or progestogens: 

These are often ineffective when menorrhagia is due to fibroids but a trial may be appropriate, particularly in women approaching the menopause.  

  • GnRH Agonists: 

Fibroids are thought to be largely oestrogen dependent, and GnRH agonists given continuously reduce gonadotrophin and subsequently oestrogen release. Initially a rise in gonadotrophins is seen as would be expected, however over time there is a down regulation of pituitary GnRH receptors causing this paradoxical fall in gonadotrophin levels. 

GnRH agonists have been shown to be effective in reducing uterine size, and inducing amenorrhoea by producing a menopause-like state. However patients are not spared the menopausal side effects of a hypo-oestrogenic state and there is a significant increase in risk of developing osteoporosis in long term use. For these reasons GnRH agonists have developed a niche role as a bridging therapy whilst patients await surgery. Their place here though is invaluable; studies have shown that if surgery is preceded by therapy with GnRH agonists Haemoglobin and haematocrit values are greatly improved and operative time and recovery are reduced.

 

Mechanism of action of medical therapies used to treat fibroids
  •  Danazol:

An androgenic steroid that inhibits GnRH secretion and thus reduces gonadotrophin secretion. It induces amenorrhoea and therefore prevents anaemia, without any significant effect on uterine size. Its’ main advantage over GnRH agonists is that the effects persist after withdrawal of therapy.

 

3. Surgical Management:

Hysterectomy has been the traditional surgical treatment for uterine fibroids.  The procedure is curative and removal of the uterus prevents recurrence.  Occasionally it is possible to perform a vaginal hysterectomy, however the likelihood of a symptomatic fibroid being small enough to permit this is quite small, and an abdominal procedure is normally required.  There is a high rate of patient satisfaction and symptom relief following the procedure.  Ovaries can be retained to prolong exposure to endogenous androgens, however they are often removed to prevent malignant change. 

The main disadvantage of hysterectomy is that it renders the woman infertile and as the condition primarily affects women of childbearing age this can be extremely undesirable.  For this reason a number of other surgical options have been developed. 

 

Myomectomy allows retention of the uterus and thus fertility.  However there is a significant (approximately 50%) recurrence rate after 5 years.  The procedure may be done laparoscopically in women who have a uterine size less than 16 weeks and less than three lesions; however an abdominal approach would usually be required. It is only possible in women whose fibroids are confined to the myometrium.

 

UAE (Uterine artery embolisation) works by ablating the blood supply to the leiomyoma, causing it to shrink.  Around 90% of patients report a symptomatic improvement however the rate of subsequent hysterectomy is high; estimates range from 20-50%.   The procedure is performed using a catheter in the femoral artery under local anaesthetic and so carries less risk than a hysterectomy which would require a general anaesthetic.  No studies have compared UAE to myomectomy or hysterectomy for long term outcome, nor has the rate of subsequent conception in those who wished to retain fertility been assessed adequately.  

 

Bibliography and Suggested Reading

Lynch AM, Morton CC . Uterus: Leiomyoma. Atlas Genet Cytogenet Oncol Haematol. May 2007.

Okolo S.  Incidence, aetiology and epidemiology of uterine fibroids.  Best Practice & Research Clinical Obstetrics and Gynaecology 2008;22(4):571–588.

Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT.  Risk Factors for uterine fibroids: reduced risk associated with oral contraceptives.  BMJ 1986; `293:359-362.

Stewart EA.  Uterine fibroids.  Lancet 2001; 357:293-298. 

Gupta S, Manyonda IT.  Acute complications of fibroids.  Best Practice & Research Clinical Obstetrics & Gynaecology  2009;23(5):609-617 

Vessey MP, Villard-Mackintosh L, McPherson K, Coulter A, Yeates D.  The epidemiology of hysterectomy: findings in a large cohort study.  Br J Obstet Gynaecol 1992;99:402-407.

Rang HP, Dale MM, Ritter JM, &Flower RJ.  Pharmacology.  6th ed, pp 453.  Philadelphia:  Churchill Livingstone Elsevier, 2007. 

Manyonda I, Sinthamoney E, Belli AM.  Controversies and challenges in the modern management of uterine fibroids.  Br J Obstet Gynaecol 2004; 111:95-102.

Carlson KJ, Miller BA, Fowler FJ Jr.  The Maine Women’s Health Study: I, outcomes of hysterectomy.   Obstet Gynecol 2000; 95:319-326

Fedele L, Parazzini F, Luchini L, Mezzopane R, Tozzi L, Villa L.  Recurrence of fibroids after myomectomy: a transvaginal ultrasonographic study.  Hum Reprod 1995; 10:1795-1796.

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