Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features
S.O. Okolo1,2,3,
C.C. Gentry1,2,
C.W. Perrett2 and
A.B. Maclean2
1 Department of Obstetrics and Gynaecology, North Middlesex University Hospital, London N18 1QX and 2 Department of Obstetrics and Gynaecology, Royal Free Campus, RFUCMS, London NW3 2PF, UK
3 To whom correspondence should be addressed. Email: s.okolo{at}medsch.ucl.ac.uk
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Abstract
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BACKGROUND: Although uterine fibroids are very common, their pathogenesis and clinical behaviour are poorly understood. Since they may be prevalent in some families, we investigated whether such a prevalence was associated with distinctive clinical and molecular features. METHODS: A casecontrol questionnaire study of 300 multi-ethnic women with uterine fibroids at a London university hospital was undertaken, with review of case notes and immunohistochemical determination of vascular endothelial growth factor (VEGF-A) in fibroids. RESULTS: When compared with families with sporadic fibroids, familial prevalence of fibroids was associated with a higher incidence of abdominal swelling (59.1% versus 41.6%; P=0.037), menorrhagia (84.4% versus 51.9%; P=0.042), dysmenorrhoea (64.4% versus 46.3%; P=0.004), dyspareunia (43.2% versus 27.9%; P=0.012) and family history of cancers (52.3% versus 32.4%; P<0.01). The fibroids were also more multiple (mean ± SEM: 7 ± 0.86 versus 3 ± 0.42; P<0.011) and strong VEGF-A expression in fibroids was more common in the familial group (64% versus 28%). Racial distribution was the same in both groups (blacks 49%, whites 33.4%, others 18.6%). CONCLUSIONS: Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features that differ from those found when fibroids occur sporadically in families.
Key words:
angiogenesis/clinical features/familial prevalence/fibroids/VEGF-A
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Introduction
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Uterine fibroids are the most common genital tumours in women, yet their behaviour is poorly understood. For example, it is not clear why fibroids in some women remain small, isolated and slow growing, but in others are large, multiple and rapidly growing. There is anecdotal evidence to suggest that close female relatives of women with fibroids often present with the condition. Women from families in which two first-degree relatives have fibroids have a two-fold increased risk of developing uterine fibroids (Vikhlyaeva et al., 1995
; Alam et al., 2001
). A 69% likelihood of heritability of uterine fibroids has been predicted from twin-pair studies, using likelihood model fitting analysis and Cox proportional hazards modelling (Snieder et al., 1998
). Although familial predisposition has also been reported in other gynaecological disorders such as endometriosis (Moen and Magnus, 1993
), polycystic ovaries (Govind et al., 1999
) and premature ovarian failure (van-Kasteren et al., 1999
), there is no study of the comparative clinical and molecular features of uterine fibroids with a familial prevalence and those without. In one study of Japanese middle-aged women, a positive first-degree history of fibroids was more common in women who had fibroids than in those without (31.5% versus 15.2%) (Sato et al., 2002
). We therefore designed a study to determine whether familial prevalence of uterine fibroids is associated with a discernible pattern of clinical features. Since we have previously demonstrated that the potent angiogenic stimulator, vascular endothelial growth factor (VEGF-A), is highly expressed in fibroids (Gentry et al., 2001
), we also investigated whether the pattern of VEGF-A expression in fibroid tissue was different between the two groups.
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Materials and methods
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Women with fibroids seen at our hospital were included in this study if they gave informed consent and had at least two first degree adult female relatives whose medical records were available or who could be contacted. The study was approved by our local research ethics committee. Familial prevalence was defined as the occurrence of fibroids, confirmed on ultrasound or histology, in at least two first degree adult female relatives of the index woman. Control women (sporadic cases) were those whose first degree adult female relatives did not have fibroids. Of 300 consenting multi-ethnic women who met the inclusion criteria, 45 (15%) had a familial prevalence of fibroids whilst 255 (85%) did not. A self-completed structured questionnaire using non-medical terms was used to obtain detailed information from the women on their medical, social and family history, including any family history of cancer or diabetes. The questionnaire relied on each woman's account of her symptoms. Case notes of 93 women (31 familial and 62 sporadic) who had myomectomy or hysterectomy between 1995 and 1999 were reviewed for operative findings, and 23 women (seven familial and 16 sporadic) had abdominal myomectomy, 14 (four familial and 10 sporadic) had hysteroscopic myomectomy and 56 (20 familial and 36 sporadic) had hysterectomy by various routes. Each woman discussed with her clinician whether surgery was indicated and agreed the type of surgery without the involvement of the research team. The group to which each woman belonged was not determined prior to surgery, as the questionnaires were analysed in batches at a later date. VEGF-A expression was determined in fibroid specimens from an unselected subset of 25 women from each group. VEGF-A was investigated by immunohistochemistry using a monoclonal antibody after protease digestion, as described previously (Gentry et al., 2001
), and was regarded as positive if 10 or more focal areas/cm2 were present, or strongly positive if 20 or more focal areas/cm2 were present. Association between independent samples was determined by comparison of means and that between two categorical variables by
2-test.
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Results
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There was a significantly higher incidence of abdominal swelling (59.1% versus 41.6%; P=0.037), menorrhagia (84.4% versus 51.9%; P=0.042), dysmenorrhoea (64.4% versus 46.3%; P=0.004) and dyspareunia (43.2% versus 27.9%; P=0.012) in women with familial prevalence of fibroids compared with those without (Table I). More women in the familial prevalence group had a family history of cancer (52.3% versus 32.4%; P<0.01), mainly tumours of the breast (19% versus 4.3%; P<0.01) and of the stomach and oesophagus (16.7% versus 3%; P<0.01). Some 24.4% of the familial group and 17% of the sporadic group were nulliparous at presentation. There was a distinct racial distribution of uterine fibroids, with more blacks (49%) in the study population than whites (33.4%) or other ethnic groups (18.6%), but the racial proportions were the same in the two groups of women (familial and sporadic). There was no difference between the two groups in the mean age at presentation, obesity (body mass index
25 kg/m2), miscarriage rates, a history of pelvic pain or a family history of diabetes.
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Table I. Findings from questionnaire study, case notes review and immunohistochemistry study in 300 women with uterine fibroids
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In the 93 women that had surgery, the most common indications for surgery were menorrhagia (23 familial and 33 sporadic), abdominal swelling (five familial and seven sporadic) or infertility associated fibroids (two familial and five sporadic). Preoperative haemoglobin was similar in both groups (mean ± SEM: 12.6 ± 0.25 g/dl versus 12.3 ± 0.18 g/dl). Mean postoperative haemoglobin change was also similar between the two groups. The number of fibroids removed at myomectomy or hysterectomy was higher in the familial group compared with the sporadic group (mean ± SEM: 7 ± 0.86 versus 3 ± 0.42; P<0.0001). The location of all the fibroids was not documented in many cases, but there was no statistical difference between the two groups in the mean size of the largest fibroid (or the only fibroid in single cases): 6.65 cm (SEM 0.59) in the familial group and 7.77 cm (SEM 1.56) in the sporadic group. Strong VEGF-A expression was more common in fibroid specimens from the familial group (64% versus 28%; P=0.011).
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Discussion
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This study indicates that familial prevalence of uterine fibroids is associated with a different pattern of clinical features and VEGF-A expression when compared with fibroids that occur sporadically in families. The 15% incidence of familiality in our multi-ethnic population is lower than the 24.7% incidence (Vikhlyaeva et al., 1995
) previously reported in a Caucasian population, probably for several reasons. We included only first-degree relatives, not both first- and second-degree relatives. We employed a robust criterion for ascertaining fibroid prevalence by seeking confirmation of diagnosis in relatives. It is also possible that heritability of uterine fibroids may be modulated by non-genetic factors and so result in varying incidence of familiality in different environments. Thus, a recent Finnish twin-pairs study has demonstrated that reproductive and anthropometric factors may play as significant a role in fibroid pathogenesis as genetic factors (Luoto et al., 2000
). It would appear, however, that this heritability of fibroids is not race-dependent, since the racial distribution of women in both our familial and sporadic groups was similar.
Familial prevalence was associated with a multiplicity of fibroids, which may explain the common clinical presentation of abdominal swelling in such women. It has also been reported recently that the higher the number of fibroids, the higher the incidence of menorrhagia. Finally, pelvic over-crowding by multiple fibroids may explain the higher incidence of dyspareunia in these women. The different rates of dysmenorrhoea between the two groups of women may be due to variations in the release of prostaglandins and vasoactive substances that mediate this complaint. Further studies are necessary to determine whether VEGF-A plays any role in the release or action of these vasoactive substances. Since menorrhagia often leads to anaemia, fatigue and sickness absence from the workplace, the socioeconomic impact of fibroids, particularly those with familial prevalence, cannot be over-estimated. It is possible that women may present with symptoms learned from their relatives who had fibroids, thus causing an over-reporting bias in the familial group. Such peer experience is likely to be marginal and would not explain symptoms such as dyspareunia, nor would it explain the differences between the two groups in the numbers of fibroids and in VEGF-A expression. Moreover, the objective of this study was to compare the symptoms that women with fibroids present with, between those with a familial prevalence of fibroids and those without. In those that went on to have surgery on clinical grounds, the outcome was again compared between the two groups. The findings are therefore unbiased, although it is unclear whether the biology of the tumour as evident in the VEGF-A differences is directly responsible for the coping behaviour of the patients as manifested in their presentation for surgery.
Monoclonal studies indicate that each fibroid develops from a single cell, but what determines the transformation from a normal to an abnormal myocyte is not known (Townsend et al., 1970
; Hashimoto et al., 1995
). Several studies have demonstrated non-random gene-directed chromosomal and cytogenetic alterations in fibroid specimens, but the results are inconsistent with regards to the incidence of such changes, their correlation to tumour size and whether such gross re-arrangements are primary or secondary events in the development of fibroids (Ligon and Morton, 2001
). Our current findings indicate that whatever triggers the transformation to an abnormal myocyte is more common or stronger in families with a prevalence of fibroids, leading to twice the number of such tumours when compared with families in which fibroids occur sporadically. Future studies on the pathogenesis of fibroids should therefore reflect these differing patterns, since it is possible that some fibroids may develop in response to inherited genes and so exhibit a familial prevalence, whilst some may develop in response to acquired gene alterations and so occur sporadically. If replicated with serum or urine VEGF-A, then our finding that strong VEGF-A expression was twice as common in fibroids with a familial prevalence as in those without could herald identification of a surrogate marker for familiality of fibroids and development of novel therapeutic options. However, irrespective of familiality, fibroid tumour size does not seem to depend on the degree of VEGF-A expression, thus confirming our previous findings (Gentry et al., 2001
).
Finally, the predominance of cancers of the breast and upper gastrointestinal tract in families with a prevalence of fibroids may be relevant clinically, but the numbers are too small to determine the reasons for this association and its implications.
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Conclusions
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The prevalence of uterine fibroids within families is associated with distinct clinical and molecular features which indicate that such tumours may be different from those that occur sporadically.
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Acknowledgements
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C.C.G. was sponsored by an educational grant from the North London Nuffield Hospital, Enfield EN2 7PR, UK.
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Submitted on January 9, 2005;
resubmitted on February 19, 2005;
accepted on March 22, 2005.