• 1.
  

  a) T b) T c) F d) F e) F

Several studies, including the Nurses’ Health Study and Black Women’s Health Study have reported that increasing parity is associated with a decreased likelihood of developing leiomyomas. However, there is a concern that the inverse association between parity and fibroid development may be an artifact of reverse causation. In this circumstance if leiomyomas were to cause infertility and reduced parity, nulliparous women will appear to be more at risk of leiomyoma and parity will appear to be associated with a reduced rate of leiomyoma. As a result, the association between parity and leiomyoma development is difficult to interpret due to the presence of potential reverse causation and other selection biases in many prospective studies. An increased incidence and severity of disease has been consistently reported by several independent investigators over the past decade in several large prospective observational studies including the Black Women’s Health Study, The Nurses’ Health Study, and the National Institute of Environmental Health Sciences Uterine Fibroid Study. It has been estimated that approximately 80% of women of African descent have uterine leiomyomas compared to 70% of Caucasian women. Multiple studies over the past decade have demonstrated an association of early age of menarche with the risk of developing leiomyomas. However, differences in study endpoints, control groups, reference age for early menarche, and overall research design for previous studies have made it difficult to confidently interpret the association of early menarche with an increased risk for leiomyomas. Associations between the incidence of leiomyoma and lifetime habits/exposures such as smoking, hormonal contraceptives, alcohol and caffeine intake and dietary factors have been assessed in several large prospective observational studies. Recent data has implied an association between Vitamin D deficiency and an increased risk of uterine leiomyoma development. However, these findings are preliminary and have not been confirmed in large prospective observational studies. To this end, the association of lifestyle exposures and factors with the incidence of leiomyomas have not been consistently observed and have not been validated by independent investigators.

• 2.
  

  a) T b) T c) T d) T e) T

Specific microRNAs (miRNAs), have been implicated in the epigenetic regulation of key genes whose protein products contribute to the pathology of leiomyoma. These stable single stranded RNAs regulate gene expression via gene silencing with either inhibition of translation, degradation of target messenger mRNA or even promote gene transcription, albeit rare. A concept that is under appreciated is that a single miRNA may have multiple targets and have different affinities for these targets. Moreover, while some miRNAs have been implicated in the regulation of genes known to promote growth of malignant tumors, there is no direct evidence to support a role for any specific miRNA in the genesis of human leiomyomas. Differential DNA global hypo-methylation was found between leiomyoma and adjacent myometria. It is postulated that hypo-methylation allows uncontrolled gene transcription allowing the aberrant expression of genes implicated in promoting the growth of leiomyomas. However, despite the mounting evidence to support methylation and demethylation as a significant epigenetic process contributing to the pathology of leiomyomas, there are no known functional proof of concept studies for a functional role in the genesis of leiomyomas. Exomic sequencing of human uterine leiomyomas identified tumor specific mutations in the mediator complex subunit 12 (MED12) gene. Further, it has been revealed that with a frequency range of 50 to 85%. MED12 is the most frequently mutated gene in uterine leiomyomas. The bulk of the reported MED12 mutations have been identified in either exon 1 or exon 2. Overall, the frequency at which MED12 is mutated provides evidence to suggest it may serve as a causal agent. However, direct evidence supporting the concept that it is a causal agent is yet to be reported. RE1 transcription factor (REST) is a transcription repressor that silences a number of genes. Of significance, REST can transcriptionally repress GPR10 in normal myometrial cells and the loss of REST promotes GPR10 expression. GPR10 was up-regulated in a subset of leiomyoma patient samples. A mouse transgenic model that overexpresses GPR10 in the myometrium develop phenotypic features that are seen in human leiomyoma, including myometrial hyperplasia and excessive extracellular matrix deposition. Whether loss of REST and subsequent increase in GPR10 can be a causal factor or merely contributes to the growth of leiomyoma cells by augmenting PI3K/AKT/mTOR signaling is yet to be determined.

• 3.
  

  a) F b) T c) F d) T e) T

African–American women have been observed to have a three-fold greater prevalence of fibroids from 18–30 years of age compared to Caucasian women and develop symptoms 10–15 years earlier than Caucasian women of similar age. African–American women are more likely to have a greater number of leiomyomas and a larger uterus at the time of diagnosis, more likely to undergo hysterectomy, less likely to undergo a minimally invasive approach, and more likely to experience postoperative complications following surgery for uterine fibroids.

• 4.
  

  a) T b) T c) T d) F e) T

Oestrogen is essential for fibroid growth, therefore antagonizing oestrogen action will inhibit their growth. Progesterone is also essential for fibroid growth, therefore antagonizing progesterone action will also inhibit it. By removing the ovaries, estradiol and progesterone levels will decrease and therefore tumor growth will be interrupted. Oral contraceptive pills block pituitary gonadotropin secretion and inhibit ovarian endocrine activity, but the pills replace ovarian sex steroids and therefore they do not induce fibroid regression. Gonadotropin-releasing hormone analogues block the pituitary-ovary axis and therefore inhibit estradiol and progesterone secretion and arrest fibroid growth.

• 5.
  

  a) F b) T c) F d) F e) F

KLF11 is a transcription factor that inhibits cell proliferation. It is stimulated by mifepristone and mildly inhibited by progesterone. AKT is a protein kinase that mediates the mitogenic effects of steroid hormones, whereas PDGF, TGFβ3 and EGF are growth factors that stimulate cell proliferation.

• 6.
  

  a) T b) F c) F d) T e) T

Normal parameters have been redefined by FIGO. Normal is considered a frequency of 24–38 days, inter-cycle variation of 2 to 20 days, duration of flow of 4.5 to 8 days and volume of flow of 5–80ml. However ‘heavy’ is also considered ‘excessive menstrual blood loss which interferes with a woman’s physical, social, emotional and/or material quality of life’.

• 7.
  

  a) T b) T c) T d) F e) T

The incidence of fibroids increases with age, as does polyps, adenomyosis, malignancy and ovulatory dysfunction. The risk factors for fibroids do not increase in line with the incidence of coagulopathies although large fibroids may result in venous thromboembolism requiring anticoagulation and thereby precipitating AUB.

• 8.
  

  a) T b) F c) T d) T e) F

The increase in vascular flow is thought to contribute to AUB by overwhelming platelet function. PAI-1 and anti-thrombin III are both decreased and this may be related in part to the reported increased levels of TGF-β described in women with fibroids. Submucosal fibroids are associated with increased rates of AUB but the evidence for this is now slightly less compelling than previously thought.

• 9.
  

  a) F b) F c) T d) T e) T

Activin-A is a growth factors belonging to the transforming growth factor family. Ovarian hormones are able to modulate growth factor expression. Growth factors are differentially expressed in leiomyomas compared to normal myometrium and regulate cellular processes such us proliferation, differentiation, angiogenesis, inflammation and fibrosis, that lead to leiomyoma formation and growth.

• 10.
  

  a) T b) T c) T d) T e) T

Current medical treatments such ulipristal acetate and potential therapeutic options such as genistein, curcumin, tranilast and vitamin D, reduce cell proliferation and also reduce extracellular matrix production. The current medical treatments above plus GnRHa, EGF-R blocker, TGF-α inhibitor and AKT inhibitor regulate growth factors and their signalling pathways. GnRH and ulipristal acetate modulate angiogenesis.

• 11.
  

  a) T b) T c) T d) T e) T

All of the described characteristics are typical of myoma appearance on ultrasound.

• 12.
  

  a) T b) T c) T d) F e) F

The first three characteristics mentioned are fundamental in describing submucous myomas. Grading aids subsequent approach to management, the minimal free myometrial margin is a reflection of location in the cavity and the percentage intra-cavity growth also aids approach to management and is part of grading. The endometrial appearance should always be commented on regardless of the presence of fibroids, though it may well be more difficult to do so with submucous fibroids. Feeding vessels are irrelevant to their evaluation.

• 13.
  

  a) T b) T c) T d) F e) F

Large solid masses with rapid interval growth and loss of shadowing are suggestive of sarcoma without being diagnostic. Radial stripes are a feature suggestive of adenomyosis. Vascularization is not a parameter that can differentiate benign from malignant myometrial tumours.

• 14.
  

  a) T b) T c) T d) T e) F

Unless uterine origin is certain on TVS/TAS, MRI is required to exclude ovarian fibromas or other mesodermal tumours e.g. gastro-intestinal stromal tumours (GISTs). If the diagnosis is uncertain then further imaging is required as it may help diagnosis as well as check for the presence of metastatic disease. Once there are more than 3–4 fibroids, ultrasound assessment is very difficult and an alternative view is needed. MRI is indicated prior to embolization to exclude contraindications such as pedunculated fibroids. Fertility itself is not an indication for MRI.

• 15.
  

  a) F b) T c) F d) F e) F

Most published studies have shown an increased risk of fetal malpresentation of about 2.5 times in the presence of fibroids.

• 16.
  

  a) T b) F c) F d) F e) F

Submucous fibroids are consistently associated with the risk of negative pregnancy outcomes whereas all of the other types have no consistent negative effect.

• 17.
  

  a) F b) F c) T d) F e) F

GnRH analogues were one of the first drugs approved by the FDA for short-term medical management of leiomyomas. Due to its side effect profile, the administration of GnRH analogues should be limited to 3–6 months. GnRH analogues have been shown to decrease bone mineral density with long-term use, due to the hypoestrogenic state (pseudomenopause) that takes place. All of the other agents listed have not been shown to be associated with changes in bone mineral density, although long-term use of ulipristal acetate should be limited in the management of leiomyomas due to the effects it has on the endometrium.

• 18.
  

  a) F b) F c) F d) T e) F

GnRH analogues are one of the most effective forms of medical management of leiomyomas, causing a 30-65% reduction in leiomyoma size. GnRH antagonists have also been effective in reducing leiomyoma size as early as 3 weeks after initiating treatment. The PEARL I and PEARL II studies demonstrated that Ulipristal acetate reduced leiomyoma volume. The LNG-IUS has been shown to be effective for long-term control of heavy menstrual bleeding, however studies have not shown any effect on fibroid volume. Danazol, although not commonly used due to its side effect profile, has been shown to reduce leiomyoma size and uterine volume.

• 19.
  

  a) T b) T c) T d) T e) F

In Europe and Canada, UPA is licensed for use at a dosage of 5mg/day for 3 months for pre-operative management of reproductive aged women with symptomatic leiomyomas. Both the PEARL I and PEARL II studies investigated ulipristal acetate at doses of either 5mg/day or 10mg/day for three months. Both treatment groups had similar rates of improvement in menstrual blood loss. PEARL II was a double blinded, non-inferiority trial that included 307 patients randomly assigned to 5 or 10 mg of UPA versus a GnRH agonist (depot leuprolide acetate) for 3 months. Pictorial blood loss assessment charts were used to assess menstrual blood loss, and the reduction in uterine bleeding was comparable in all three groups, occurring in 98% of those receiving 10mg UPA, 90% for 5mg of UPA, and 89% for leuprolide acetate. Similar reductions in uterine leiomyoma volume were also noted in the 5mg and 10mg UPA groups. Because of the reported side effects, and endometrial changes (physiologic endometrial changes), ulipristal acetate therapy is limited to 3 months at a dose of 5mg/day in Europe and Canada. To date, in the United States, UPA is approved by the FDA for use only as an emergency contraceptive.

• 20.
  

  a) T b) T c) T d) T e) F

SPRMs have tissue-specific effects at progesterone receptors (PRs), and can be full PR agonists, antagonists, or have a mixed agonist/antagonist profile. They have been proven to be effective in the management of symptomatic leiomyomas. Mifepristone, asoprisnil, and telepristone are all SPRMs, which show promise in the treatment of symptomatic leiomyomas. Ulipristal acetate is a SPRM that is very effective in reducing menstrual blood loss and decreasing leiomyoma size, and in some studies has been shown to be comparable to GnRH agonists in efficacy. Further investigation is needed to determine long-term efficacy and safety of all of these SPRMs in the treatment of symptomatic leiomyomas. Pirfenidone is not a SPRM. It is a growth factor modulator being investigated for the potential medical management of fibroids through its anti-fibrotic effects and its ability to regulate the formation of extracellular matrix. In vitro studies have demonstrated its efficacy in reducing myometrial/leiomyoma cell proliferation and decreasing the expression of the mRNA of collagen I and III in a dose-dependent manner without any cytotoxic effects.

• 21.
  

  a) F b) T c) T d) F e) F

No data are available for myomectomy and the issue of whether GnRH analogues make the process of “shelling out” a fibroid difficult has not been answered by published trials. Change in uterine volume and fibroid volume, in the no treatment trials and uterine volume (the latter 2 outcomes were not assessed) in the placebo trials in patients treated with GnRH analogues were significantly reduced (for all trials combined, WMD=−159ml, 95% CI −169 – −149, WMD=−2.2 gestational weeks, 95% CI −2.3 – −1.9 and WMD=−12mls, 95% CI= −18.3 – −6.6 respectively). Pre-operative haemoglobin and haematocrit were significantly increased after GnRH analogue treatment when compared with no treatment and haemoglobin was significantly increased after GnRH analogue treatment in the placebo trials (for placebo and no treatment trials combined, WMD=1.0g/dL, 95% CI 0.7–1.2 and WMD=3.1%, 95% CI 1.8–4.5 respectively). This may be important in women with severe menorrhagia and anaemia, though a weighted mean increase of 1.3 g/dl for haemoglobin concentration and 3.1% for haematocrit may be of relatively little clinical importance in many cases. No study focused on this point. However, in the studies where it has been reported, both the choice of surgical approach (vaginal vs. abdominal) and type of incision (midline vs. transverse) are altered favourably with the use of GnRH analogues, presumably as a consequence of the reduction in uterine volume. This suggests that these agents may be useful pre-operatively for women where an abdominal hysterectomy or midline incision is being proposed because of uterine size. The duration of the surgery for myomectomy did not differ between treatment groups and control group (WMD 4.20 min, 95% CI −2.69, 11.08).

• 22.
  

  a) F b) F c) F d) F e) T

The usefulness of misoprostol has been studied in 3 meta-analyses. Regardless of the route of administration (meaning vaginal, oral or sublingual route), misoprostol was more efficient than placebo for cervical dilatation in pre-menopausal women. However, Misoprostol was associated with more side effects (cramps, nausea, diarrhoea) and not associated with less complication. In a recent meta-analysis, Kamath et al. analyzed the benefit of GnRH analogue use before hysteroscopic fibroid resection. Including 2 studies (86 patients), they founded significant differences in operative duration and diminution of fluid absorption in favor of GnRH use but no advantage of GnRH administration concerning the rate of complete resection of submucous myomas. Berg et al. in a prospective randomized trial, that compared monopolar vs. bipolar energy in 192 patients, observed a higher drop of serum sodium in the monopolar group without any difference between both groups in term of adverse events. Bahar et al. in a case control study which included 1842 hysteroscopic procedures for any indication (15.8 vs. 12.6% myomectomy) compared complications associated with bipolar and monopolar resection. They found a similar complication rate in both groups (4.1% (55/1318) in the bipolar group vs. 2.8% (15/524), p=0.08). No studies have reported pregnancy rates following myoma hysteroscopic resection. Over 6 cm diameter, hysteroscopic management was associated with an increased rate of secondary procedure and longer recovery time [OR 14 95%IC 1.3–156] than smaller ones.

• 23.
  

  a) F b) F c) F d) F e) T

The gold standard still remains myomectomy especially in cases where patients wish to conceive. Non-surgical treatments claim a good effectiveness, short or absent hospital stay, minimal invasiveness and low complications but are much more dependant on myoma characteristics when compared with myomectomy.

• 24
  

  . a) F b) F c) F d) T e) F

The selection criteria pay a pivotal role when scheduling a patient for UAE to avoid complications and to have a good clinical result. Possible relative contraindications could be the presence of a pedunculated or submucosal myoma, previous internal iliac or uterine artery occlusion or recent GnRH analogue administration. The use of UAE in cases of pedunculated fibroids that present a stalk 50% narrower than the tumour remains controversial. Even though a few series have reported the treatment of pedunculated myomas as safe, embolization may cause torsion of the fibroid with subsequent separation of the tumour from the uterus or septic complications requiring surgical removal.

• 25.
  

  a) T b) T c) T d) F e) F

Treated myomas showed a progressive shrinkage during follow-up, with a reduction percentage after 1 month of 22.2%, after 3 months of 37.5% and after 6 months of 52.6%.

• 26.
  

  a) F b) F c) F d) T e) F

Nowadays MRgFUS is not recommended for those patients who wish for future pregnancy and additional studies are needed to evaluate safety profiles compared with other techniques. Initially patients with a desire of future fertility were excluded but an increasing number of case reports and case series are reporting successful uncomplicated pregnancies after MRgFUS.

• 27.
  

  a) F b) F c) T d) T e) F

An increasing number of case reports and case series are reporting successful uncomplicated pregnancies after MRgFUS. A case series reported 54 pregnancies in 51 women after MRgFUS treatment of uterine leiomyomas with a mean time to conception of 8 months after treatment. Live births occurred in 41% of pregnancies, the spontaneous abortion rate was 28%, and the elective pregnancy termination rate 11%. The vaginal route was the preferred one with a 64% vaginal delivery rate.

• 28.
  

  a) T b) T c) F d) T e) F

The effectiveness of the MRgFUS procedure can be determined by the non-perfused volume (NPV) ratio, defined as the volume of myoma no longer perfused by gadolinium after treatment as assessed by MRI, divided by total myoma volume. The non-perfused volume (NPV) appears to correlate with the volume of histological necrosis treatment. MRI hyper-intense fibroids, more common in younger fertile women (36–40 years), were associated with a reduced treatment success compared with hypo-intense fibroids. In a review considering a 12-month follow-up of 130 clinical patients after magnetic resonance-guided focused ultrasound for uterine leiomyomas evaluating symptom relief and additional procedures, the relief of symptoms was respectively, 86% (90 of 105), 93% (92 of 99), and 88% (78 of 89) at the 3-, 6-, and 12-month follow-up. An important limitation in the use of MRgFUS is that just a fraction of patients with fibroids meet the inclusion criteria. Side effects are very uncommon.

• 29.
  

  a) T b) F c) F d) F e) F

Up to 40% of patients experience a self-limiting post-embolization syndrome that resolves in 48 hours. All of the other features are rare.

• 30.
  

  a) F b) F c) T d) F e) T

Up to 40% of women experience post-embolization syndrome. It is characterized by diffuse abdominal pain, nausea, vomiting, low-grade fever, and leukocytosis. The pain is caused by the ischemic necrosis of the fibroid and it usually resolves within a few days. In 5% to 10% it persists over two weeks amongst which the 2% will undergo a hysterectomy within 6 months.