Classification Of Fibroids And Infertility Biology Essay

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Based on their anatomical location, fibroids are classified as submucous (SM), intramural (IM) or subserosal (SS). Unfortunately, there is a lack of consensus to this division within the scientific body which makes comparison between research studies a difficult task. Bajekal and Li (2000) suggested the following definitions: SM fibroids, as described by the European Society of Hysteroscopy (Wamsteker, Emanuel et al. 1993), are those that distort the uterine cavity and can be subgrouped into: pedunculated (type 0), sessile with intramural extension of fibroid <50% ( type I) and sessile with intramural extension ≥50% (type II). IM fibroids are those which do not distort the uterine cavity and with <50% of the tumor protruding into the serosal surface of the uterus. Fibroids protruding ≥50% out of the serosal surface are classified as SS and may be sessile or pedunculated.

In addition to the location, attention should also be paid to the numbers and size of the fibroids, for this is of clinical significance.

Presentation

The vast majority of uterine fibroids are asymptomatic and do not require any treatment or follow-up other than counselling and reassurance [XXXX]. However, when symptomatic, patients complain of a multitude of symptoms comprising of: menstrual irregularities including menorrhagia, dysmenorrhoea, dyspareunia and intermenstrual bleeding; intermenstrual pain; pressure symptoms such as the sensation of 'pelvic fullness', urinary frequency or urgency, tenesmus and constipation. Large fibroids may cause hydronephrosis or bodily disfigurement. On the reproductive front, patients may present with infertility, recurrent early pregnancy loss, acute pain during pregnancy, preterm labour, malpresentation, obstructed labour leading to increased rates of caesarean section, and postpartum haemorrhage.

Fibroids and Infertility- Mechanism

It has traditionally been suggested that fibroids cause altered uterine contractility and pose a mechanical obstruction for the transport of gametes (Deligdish and Loewenthal 1970; Hunt and Wallach 1974). The same studies also suggest that impaired blood supply to the endometrium may lead to inflammation and subsequent implantation failure. Over the three decades that have elapsed since the publication of these papers, there has been no development to elucidate a mechanism by which fibroids cause infertility in this area since these reports were published

Diagnosis

While the diagnosis of fibroids is suspected on the findings of an irregularly enlarged uterus on bimanual pelvic examination, its confirmation requires additional imaging studies. A further investigation not only helps identify fibroids, but also helps identify confounding pathologies such as adenomyosis, polyps and endometriosis which may themselves cause infertility.

Hysterosalpingography (HSG) and transvaginal ultrasonography (TVUS) are the two imaging tools that have been commonly used to diagnose uterine fibroids. TVUS has traditionally been regarded as an accurate imaging modality to investigate SM fibroids. Recent studies however, put its sensitivity and positive predictive value to as low as 58% and 47% respectively (Cepni, Ocal et al. 2005). HSG, initially employed to demonstrate tubal patency, was then used to investigate abnormalities of the uterine cavity. It too paled out when compared to the 'golden standard', hysteroscopy, by registering a low sensitivity of 50% and positive predictive value of 29% for polypoid lesions (fibroids and polyps) of the uterine cavity (Soares, Barbosa dos Reis et al. 2000).

It has been established that an accurate diagnosis of fibroids is only made by way of a sonohysterogram, hysteroscopy, and magnetic resonance imaging (MRI). A study by Cicinelli (1995), though limited by the number of subjects, put the sensitivity, specificity and predictive values for sonohysterography and hysteroscopy at 100%. Advantages of using MRI are in it being less invasive, employing harmless non-ionizing radiation and being less observer dependent. Divakar (2008) identified MRI as a tool that could help differentiate between benign fibroids and malignant leiomyosarcoma. Likewise, MRI can also be employed to differentiate between fibroids and adenomyosis, the treatment for which differs from the management of fibroids. The main drawbacks for MRI are its high cost, longer investigation time and contraindication in the presence of metallic foreign bodies and implants. These disadvantages have put sonohysterography and hysteroscopy in the forefront for the investigation of fibroids, reducing the MRI for use in high quality research studies.

In their meta-analysis of twenty-three studies, Pritts et al. (2009) have suggested that in choosing TUVS and/or HSG as the imaging tools of choice, these studies may have under-reported the intracavitary involvement of IM fibroids, leading to an underestimation of the effect of SM fibroids on infertility and an overestimation of the same for IM fibroids. The need for studies to bring about uniformity in their design techniques with regards to their choice of diagnostic tools cannot be over emphasised. An incorrect diagnosis would make the comparison of treatment regiments and their stated outcomes an arduous task.

Medical Treatment

Gonadotropin-releasing hormone agonists (GnRHa) have been employed to produce a temporary and reversible hypoestrogenic state by down regulating the pituitary gonadotropin-releasing hormone receptors. One such agonist, nafarelin, was shown to decrease fibroid volume by 46% and uterine volume by 57% over a six month period (Andreyko, Blumenfeld et al. 1988). In addition to these changes, studies have looked at the effect of GnRHas treatment on the relief of symptoms such as such as bleeding and found an improvement (Schlaff, Zerhouni et al. 1989). However, with cessation of therapy, the fibroids grow back to their pretreatment volume (Friedman, Harrison-Atlas et al. 1989). In light of these observations, and due to the amenorrhea that accompanies treatment, the long-term use of GnRHas as a treatment for asymptomatic fibroids in women wishing to improve fertility is not recommended. Conversely, their pre-operative short-term use with iron supplements improves haematological parameters in women who are anaemic due to menorrhagia (Benagiano, Kivinen et al. 1996) and makes the surgical resection easier due to the decrease in size of the myomas. Once again, concern has been expressed for what may seem as a higher post procedure fibroid recurrence rate when patients treated with GnRHas undergo a myomectomy.

Radiological Interventions

Over the past two decades, there has been tremendous interest in treating fibroids by way of radiological intervention. However, success has been limited by the number of patients who have been treated, which in turn is a result of the strict and narrow eligibility criteria. For want of enough data, this has led to scepticism when treating the subgroup of patients who wish to preserve their fertility.

Laparoscopic myolysis is a procedure that involves the application of an electric current, laser or liquid nitrogen to a fibroid to coagulate its blood supply and cause subsequent necrosis and volume reduction. With this treatment, patients are discharged on the same day as the procedure with minimal scarring and a quick recovery. This treatment is suitable for fibroids that are between 3 cm and 10 cm in size. For larger fibroids, preoperative treatment with GnRHa may be helpful. In light of the postoperative complications of uterine infection and pelvic adhesion formation, this treatment is not recommended for women desirous of fertility. Several cases of successful pregnancies post myolysis have been reported in the medical literature (Ciavattini, Tsiroglou et al. 2006) PARK, JO 2008, as have a number reports on uterine rupture during pregnancy (Vilos, Daly et al. 1998; Nkemayim, Hammadeh et al. 2000). Hence it would be prudent to avoid pregnancy after myolysis treatment, or else follow-up with great care.

Recently, the advent of uterine artery embolization (UAE) as a minimally invasive angiographic technique to treat symptomatic fibroids has caught a lot of attention. This procedure shrinks fibroids by occluding their blood supply by the introduction of embolic agents through a catheter placed in the uterine arteries via the common femoral artery. Although promising in its goal to reduce the size of fibroids, and hence their symptoms, UAE presents numerous drawbacks for women wishing to maintain their fertility post procedure. Despite the low rates of complications, it bears keeping in mind that a hysterectomy might be needed to manage complications such as uterine necrosis or general sepsis (Godfrey and Zbella 2001; Walker and Pelage 2002). To date, five fatalities following UAE have been reported, two of which, in the UK (Vashisht, Studd et al. 1999) and the Netherlands (de Blok, de Vries et al. 2003), were due to septicaemia. The other three were as a result of pulmonary embolism or uncertain causes, which in all cases were unrelated to the procedure.

Amenorrhea, as a complication of concern for infertile patients and those planning a subsequent pregnancy is reported at a rate of 3% for patients under the age of 40 years (Pron, Bennett et al. 2003) . This amenorrhea may be permanent and is either due to inadvertent ovarian artery embelectomy (Ryu, Siddiqi et al. 2003) or endometrial atrophy as a result of endometrial ischemia (Tropeano, Litwicka et al. 2003).

With pregnancy rates being the outcome of concern for any intervention to manage fibroids in the infertile patient, it is reassuring to note that studies have demonstrated success rates equal to those reported for women undergoing an a myomectomy. Walker and McDowell (2006) reported a pregnancy rate of 30.5% for 108 women wishing to get pregnant post UAE. Another study, although limited by the sample population it followed, put this figure at 83% (Kim et al. 2005). While these figures are encouraging, the number of studies reporting them is too few to conclude substantially. On the other end of the spectrum, Homer and Saridogan (2009) reported a higher miscarriage and caesarean delivery rate after UAE, similar to the findings of an earlier study by Walker and McDowell (2006). This prompted the Royal College of Obstetricians and Gynaecologists to put out a word of caution by way of a press release (RCOG, 2009) urging caution in recommending UAE for women desirous of becoming pregnant. Elaborating further in their updated clinical recommendations (RCOG, 2009) set out by the Joint Working Party, the RCOG advices women contemplating a pregnancy in the future to consider hysteroscopic resection or laparoscopic myomectomy over UAE for the treatment of myomectomy. However, UAE may be acceptable for the minority of patients in whom surgery is contraindicated, or those who are likely to refuse a blood transfusion or for whom previous surgery was unsuccessful. In all these latter cases, the patients ought to be appropriately counselled and made aware of all possible adverse effects.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is another organ-preserving procedure that is non-invasive and has been successfully used in the treatment of symptomatic fibroids. MRgFUS makes use of percutaneous high-energy ultrasound waves which are focused under MRI guidance into the centre of the fibroid. The heat generated causes thermablation leading to tissue necrosis and reduction in size of the fibroid. Injury to tissues lying in the path of the ultrasound beam is avoided using MRI to selectively map fibroids that would allow for the safe passage of the beam without traversing bowel or bladder. MRI also allows for the high-resolution real time mapping of thermablation injury and the visualisation of the non-perfused area using contrast-enhancement to facilitate the MRgFUS procedure and follow-up respectively. Results obtained 6 month post-treatment show a modest shrinkage in volume of 13.5% and a non-perfused volume (51 cm3) greater than the thermal dose volume at the time of treatment (36 cm3) (Hindley et al. 2004). This suggests that the effect of the injury extends beyond the target area, and yet, within the fibroid. The same study showed a great reduction in symptom severity as measured by the Uterine Fibroid Symptom and Quality of Life Questionnaire score, proving that successful outcomes are more diagnostic when assessed this way.

Some of the adverse events that have been reported for MRgFUS are skin burns at the treatment site; small bowel and bladder injuries requiring surgical repair; and neuropathies from damage to adjacent tissues (Taran et al. 2009). Patients might find it difficult to sit still throughout the procedure which may take up to three hours to complete or else feel claustrophobic in the noisy confines of the MRI machine. And yet, despite these disadvantages, MRgFUS holds great promise as a non-invasive, uterus-sparing, tissue-destructive technique of treating fibroids.

Patient selection criteria for MRgFUS are very stringent and are based on fibroid size, number, location and distance away from surface skin; presence of any other uterine pathology such as adenomyosis; and past abdominal surgery status (Yoon et al. 2008). It is no surprise that only a third of patients that are screened are selected for this procedure (Taran et al. 2009). In addition, initial trials were only restricted to premenopausal women who had to declare they were not interested in any future pregnancies. This was to safeguard these patients against any potential complications undermining their future fertility. Once initial data establishing safety of the procedure started streaming in, news on postprocedure spontaneous pregnancies resulting in the birth of healthy infants followed. Encouraged by these results, trials for infertile women trying to get pregnant and wanting MRgFUS as treatment for their fibroids were started. The results of all these efforts was reported by Rabinovici et al. (2010), documenting 54 pregnancies in 51 women who had undergone MRgFUS till 2007. The outcomes of these pregnancies was live birth in 41%, spontaneous abortion in 28%, elective termination of pregnancy in 11% and ongoing pregnancies at 20 weeks or beyond for the remaining 20%. Despite varying uterine and patient factors taken into consideration when selecting patients for MRgFUS, comparisons could be made with those undergoing UAE, especially since both groups were similar with regards to maternal age. It was concluded that the term delivery rates post MRgFUS were higher than those reported for the UAE group (93% vs. 71%-82%). Other encouraging results were a remarkably lower caesarean section rate (36% vs. 50%-73%), higher mean birth weight (3.3 kg vs. 2.9 kg) and the absence of any stillbirths or low birth weight babies (Rabinovici et al. 2010). Another noteworthy point was that this data was furnished by 14 hospitals and medical centres in seven countries around the world. Despite the limited numbers of cases reported, the results have been very encouraging and should be confirmed by additional studies. One such multicenter randomized clinical trial in the United States (NCT00730886, clinicaltrials.gov) is currently underway with an endpoint slated for July 2011. This trial is to look at the reproductive outcomes of 650 couples with unexplained infertility and at least one non-hysteroscopically resectable fibroid that distorts the endometrial cavity, when treated by MRgFUS. The control group is to be treated with myomectomy and both are to be followed up for 15 months post-treatment. If this well designed trial provides better fertility outcomes for the MRgFUS treated group, it might pave the way for the dethroning of the 'gold standard' surgical myomectomy as the treatment modality of choice for fibroids in women desiring fertility.

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