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9 Fibroids and menorrhagia
9 Fibroids and menorrhagia C H R I S T I N E P. W E S T MARY ANN LUMSDEN
Uterine fibroids, also known as leiomyomata, are common benign tumours which arise in the myometrium. They are composed predominantly of smooth muscle with a variable amount of connective tissue and have a characteristic smooth white whorled appearance when cross-sectioned. Three subtypes are recognized depending on their situation in relation to the uterine wall, namely submucous, subserous and intramural. They are commonly multiple and may result in considerable uterine enlargement (Figure 1). Leiomyomata are found in postpubertal women of all ages but are most commonly seen towards the end of reproductive life. It has been estimated that between 20 and 25% of women over the age of 35 years have fibroids (Smith C J, 1952). Fibroids are frequently asymptomatic but may be associated with infertility and pregnancy loss. The mechanism of their effect on fertility is uncertain but mechanical factors are likely to play a part through cornual
Figure 1, Multiple fibroids causing gross uterine enlargement. Hysterectomy specimen. BaiUiOre's Clinical Obstetrics and Gynaecology--Vol. 3, No. 2, June 1989
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obstruction and interference with implantation. It has been stated that fibroids are a consequence rather than a cause of childlessness (Witherspoon, 1935). Nevertheless, in women desiring pregnancy, a conception rate of 40% following myomectomy has been quoted (Buttram and Reiter, 1981). Menstrual upset (see below) is commonly attributed to the presence of fibroids and pressure effects from large tumours are frequently reported. Although they may be associated with dysmenorrhoea, fibroids are usually painless unless they undergo torsion or degeneration. FIBROIDS AND MENORRHAGIA
Fibroids are a well recognized cause of menorrhagia although the proportion associated with excessive menstrual loss is not well documented. In the above quoted review of women undergoing myomectomy (Buttram and Reiter, 1981), 30% of the women complained of menorrhagia although the proportion varied from 17 to 61% in nine individual series. In one study fibroids were diagnosed in only 10% of women complaining of menorrhagia whose measured blood loss was between 80 and 100 ml but in as many as 40% of those with measured blood loss in excess of 200 ml (Rybo et al, 1985). Nevertheless, the association between fibroids and menorrhagia has been challenged, Miller et al (1953) attributing this symptom only to the presence of submucous fibroids. The latter, however, accounted for only a quarter of cases of menorrhagia is one South African series of women with fibroids (Rubin A and Ford, 1974) and it now seems clear that heavy menstrual loss may be associated with uterine fibroids in any site. Mechanism of abnormal bleeding
The mechanism of abnormal bleeding in the presence of uterine fibroids is unknown. In the past, most cases of abnormal menstruation associated with fibroids were attributed to abnormalities of ovarian function (Miller and Ludovici, 1955), rather than to the presence of the fibroids. A reported association between uterine fibroids and hyperplastic changes in the endometrium (Deligdish and Loewenthal, 1970) has been used as more recent evidence to support a common mechanism in the aetiology of the two conditions although the same authors also described atrophic changes in endometrium from the same subjects. This mixed histological picture has been reported by others (Farrer-Brown et al, 1971) and is more likely to reflect local differences in steroid binding within the uterus rather than abnormal ovarian function. Endocrine investigation has failed to identify any abnormality of circulating ovarian steroids in women with fibroids (Spellacy et al, 1972; Maheux et al, 1986), compared with normal controls. The origin of heavy menstrual loss has been regarded as secondary to enlargement of the surface area of the uterine cavity or due to necrosis of the endometrium overlying submucous fibroids. The latter was disputed in an early study by Sampson (1913) who attributed the excessive blood loss to the presence of dilated venous plexuses in the myometrium and endometrium
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adjacent to myomata. His results were confirmed by Farrer-Brown et al (1971) who performed histological and microradiographic studies on hysterectomy specimens. Dilated endometrial and myometrial veins were a consistent finding, seen not only in proximity to individual fibroids but also some distance away and were thought to be obstructive in origin. Venous dilatation was most marked in relation to large submucous fibroids but was also present with intramural and some subserous fibroids. These dilated endometrial veins are likely to be involved in the pathogenesis of heavy menstrual loss and might explain the association of menorrhagia with intramural and subserous fibroids as well as those encroaching directly upon the uterine cavity. Abnormalities in prostaglandin production from the uterus have been implicated in both dysfunctional uterine bleeding (Smith SK et al, 1981a,b) and dysmenorrhoea (Pickles et al, 1965; Lumsden et al, 1983). Fibroids have been shown to release prostaglandins in vitro (Rees and Turnbull, 1985), the principal prostaglandin produced being 6-keto PGF1, the stable metabolite of prostacyclin. Since this is a potent vasodilator, it may contribute to the menorrhagia associated with the presence of fibroids. It has also been suggested that menstrual abnormalities related to fibroids are due to a disturbance in normal myometrial contractility (Farrer-Brown et al, 1971). Intrauterine pressure recordings made in women with fibroids prior to hysterectomy have demonstrated abnormalities of uterine activity (Iosif and Akerlund, 1983). This may reflect differences in the proportions of smooth muscle and connective tissue in fibroids compared to normal myometrium. It may also be associated with a decreased number of prostaglandin receptors in fibroids compared with surrounding myometrium (Hofmann et al, 1984a). Prostaglandins are potent stimulators of smooth muscle contractility and these differences may result in inco-ordinate smooth muscle activity. AETIOLOGY Uterine leiomyomata are thought to be oestrogen-dependent since they do not occur prior to puberty and they become smaller after the menopause. Recent studies have demonstrated a significant reduction in fibroid size in women rendered hypo-oestrogenic with agonists of luteinizing hormone releasing hormone (LHRH) (Filicori et al, 1983; West et al, 1987). Conversely, however, there is little evidence that excessive stimulation with oestrogen promotes growth of fibroids. Two studies have failed to demonstrate enlargement of fibroids during pregnancy (Randall and Odell, 1943; Aharoni et al, 1988), contrary to common belief. Similarly, although an association between fibroids, anovular cycles and endometrial hyperplasia has been described (Witherspoon and Butler, 1934), recent studies have shown no difference in ovarian activity between women with fibroids and a control group (see above). Evidence for the oestrogen stimulation theory was based on experimental work on guinea pigs given prolonged oestrogen therapy (Lipschutz, 1942).
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Benign uterine and extragenital tumours were observed and found to be inhibited by progesterone or testosterone. However critics of these experiments have pointed out that these tumours were composed of connective tissue rather than of smooth muscle (Segaloff et al, 1949) and thus differ from true leiomyomas. Fibroids are not seen in animal species and thus there is no appropriate animal model for study. Research into their nature and causation must therefore be based on human material. Oestrogen acts via receptors in the membranes of responsive cells and recent study of its mechanism of action has centred on these. Steroid receptors have been demonstrated in both myometrium and fibroid (Farber et al, 1972; Puuka et al, 1976; Wilson et al, 1980) and some workers suggest that the concentration of binding sites is greater in fibroids (Farber et al, 1972, Wilson et al, 1980). In order to elucidate the mechanism whereby oestrogen influences the growth of fibroids, we have studied the effect of the oestrogen suppression associated with L H R H agonist therapy on oestrogen receptors in fibroid and myometrium. Women with fibroids who were scheduled for hysterectomy were pre-treated for 3 months with goserelin (Zoladex), an agonist of L H R H which is administered as a monthly subcutaneous depot and which produces consistent oestrogen suppression (West and Baird, 1987). Binding of steroids to these uteri was compared with those from women with fibroids who had received no therapy prior to surgery. The receptor concentration was measured using the separation of bound from free hormone with dextran-coated charcoal which assesses unoccupied receptors and an enzyme immunoassay which is thought to measure the total number of receptors (Lumsden et al, 1989a). We confirmed the results of Wilson et al (1980) by demonstrating higher concentration of oestrogen receptors in fibroids than in the surrounding myometrium (Lumsden et al, 1989a) but we also found that both unoccupied and total receptor concentrations rose with the use of L H R H agonists (Figure 2). This was an unexpected result since the concentration of oestradiol receptors in tissues is thought to be proportional to the levels of circulating oestradiol and the latter is low in Oestradiol
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agonist treated women. As the size of the uterine fibroids was reduced by the L H R H agonist, a decrease in receptor number might have been expected in the treated women. Both unoccupied and total receptor concentrations were increased so that the results cannot be explained simply by the low concentration of circulating oestradiol. This suggests that the rise is due to an actual increase in receptor concentration and makes a direct action of oestradiol on the tissues unlikely. It is possible that oestrogen exerts an effect on fibroid growth via another factor. Epidermal growth factor (EGF) is a member of the group of peptide hormones which control the rate and extent of cell proliferation. The addition of EGF to cell cultures induces many cellular responses including morphological changes, stimulation of various active transport systems for both inorganic ions and low molecular weight metabolites, phosphoinositol turnover and the formation of macromolecules including RNA, protein and D N A (for review see Staros et al, 1985). High affinity binding sites have been demonstrated in the human uterus (Hofman et al, 1984b; Sheets et al, 1985) and in the rat uterus (Mukku and Stancel, 1985). In the rat, the binding of EGF to the uterus is regulated by oestrogen (Mukku and Stancel, 1985). Oestradiol also increases the EGF content of mouse uterus (Gonzalez et al, 1984). Oestrogen has been shown to induce the production of EGF-related polypeptides from a breast cancer cell line (Dickson et al, 1986). EGF binds to all the cell types in the human uterus but no changes have been observed during the menstrual cycle (Chegini et al, 1986). In the hysterectomy specimens described above, we found that pre-treatment with an L H R H agonist significantly decreased the concentration of binding sites for EGF in fibroid tissue but not in the surrounding myometrium (Figure 2; Lumsden et al, 1988). It is thus possible that oestradiol exerts its action on fibroid growth via an alteration of the binding of epidermal growth factor. INVESTIGATIONS Uterine fibroids are usually diagnosed clinically but there are a number of techniques which are of value in further assessment. Pelvic ultrasound (Figure 3) is now routinely performed to evaluate the nature of large masses, particularly to differentiate uterine enlargement from an ovarian lesion and to exclude pregnancy. Studies comparing ultrasound appearances with the histological nature of a pelvic tumour removed surgically have shown ultrasound to be accurate in over 80% of cases (Cochrane and Thomas, 1974; Lawson and Albarelli, 1977). The commonest source of confusion is between pedunculated subserous fibroids and solid ovarian tumours. Magnetic resonance imaging (Hricak et al, 1985) is a more accurate method of diagnosis of pelvic tumours but is expensive and less widely available. If any doubt remains about the nature of a pelvic tumour, laparoscopy or laparotomy are indicated. As well as their value for diagnostic purposes, the techniques mentioned above are valuable for serial monitoring of fibroid size during conservative management or in assessing the response to medical therapy (see below).
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Using ultrasound, the volume of spherical tumours can easily be calculated by applying the formula 4/3-r:r3 to individual fibroids or to the whole uterus (Healy et al, 1986; West et al, 1987). The accuracy of this technique has been validated by comparison of uterine volume measured by ultrasound one day prior to hysterectomy with the volume of the fresh operative specimen measured by water displacement. A highly significant correlation between the two sets of measurements was found (Lumsden et al, 1987). We found the technique to be accurate even in cases where the uterine outline was irregular. Menstrual abnormalities cannot always be assumed to be attributable to the presence of fibroids, particularly if there are disturbances in the normal
Figure 3.
Ultrasound m e a s u r e m e n t of fibroid uterus.
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cycle pattern in women over the age of 40 years. Curettage or endometrial biopsy is always indicated in these circumstances. Hysterosalpingography and hysteroscopy (Sciarra and Valle, 1977) may be helpful in the detection of submucous fibroids but are used more often in the evaluation of infertility or recurrent abortion than in the investigation of menorrhagia. As newer forms of treatment of fibroids gain popularity, accurate diagnosis with the aid of these methods may become more relevant. MANAGEMENT The management of women with uterine fibroids depends on the associated symptoms, the age and the reproductive status of the individual. Small asymptomatic fibroids rarely require intervention, provided that their nature is certain. There has been a tendency in the past to treat large fibroids surgically even when they are asymptomatic, because of possible confusion with ovarian neoplasia. This problem has been largely overcome in contemporary gynaecological practice because of the wide availability of diagnostic ultrasound (see above). Surgical treatment has also been favoured because of the theoretical risk of sarcomatous change in a fibroid. It is thought, however, that the risks have been overemphasized and that the true incidence is below 0.2% (Corscaden and Singh, 1958). Sarcomas usually give rise to pain, abnormal bleeding and sometimes systemic upset. They occur most frequently in postmenopausal women (Thornton and Carter, 1951; Hannigan and Gomez, 1979) and uterine enlargement and onset of symptoms in this age group would certainly warrant surgical intervention. Otherwise, asymptomatic fibroids can be managed conservatively, provided that adequate facilities exist for assessment and monitoring. Surgical treatment The treatment of women with fibroids associated with menorrhagia is conventionally by hysterectomy. The presence of fibroids is one of the commonest indications for hysterectomy, comprising 30% of all indications in the United States (Lee et al, 1984). In Scotland in 1985, 21% of hysterectomies were for fibroids, taking up a total of 16722 bed days with an average stay of 8.9 days (Scottish Hospital In-Patient Statistics, 1985). Conservative surgery by myomectomy is usually reserved for women desiring fertility, although many of this group may also be troubled by heavy menstruation. Of the two procedures, myomectomy carries a higher morbidity than hysterectomy and may be technically more difficult. Myomectomy in women with menorrhagia has been followed by subjective relief of this symptom in between 40 and 91% of cases (Buttram and Reiter, 1981). However further surgery is estimated to be necessary in 10% of women treated initially by myomectomy for various indications. If hysterectomy is required at a later date, it may be rendered more difficult by previous myomectomy because of the high incidence of postoperative adhesions (Rubin IC, 1942).
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Newer surgical methods
Direct visualization of subserous and intramural fibroids by laparoscopy and of submucous fibroids by hysteroscopy (Sciarra and Valle, 1977) has made the endoscopic treatment of small fibroids possible in certain circumstances. Both pedunculated and intramural fibroids may be removed laparoscopically with the aid of eleetrocoagulation (Murphy, 1987), although this technique is unlikely to be relevant to the management of women with menorrhagia. Submucous fibroids may be removed vaginally if prolapsed or resected under hysteroscopic visualization using an electrical loop (Hallez et al, 1987) although use of the hysteroscope is less popular in the United Kingdom than in the United States. There have been a few reports of the successful use of ablation or coagulation of the endometrium with the neodymium-yttrium aluminium garnet (Nd-YAG) laser in women with menorrhagia (Goldrath et al, 1981; Lomano, 1986) and this technique may be applicable to small submucous fibroids. However the procedure is timeconsuming, technically difficult to master (Davis, 1987) and currently of limited availability (see Chapter 12). Medical treatment of uterine fibroids
There is considerable demand for an alternative to surgery in the management of uterine fibroids. This is not confined to women desiring pregnancy. Many women have serious objections to hysterectomy and this is important in certain racial groups where the prevalence of fibroids may be particularly high (Witherspoon and Butler, 1934). Psychological sequelae of hysterectomy, although uncommon, are well documented (Richards, 1973) and there is well recognized surgical morbidity. There are also important economic considerations as more women assume positions of responsibility within society and in families where the woman is the major breadwinner. Ideally, medical therapy should control symptoms and cause shrinkage and degeneration of the fibroids, leading to their eventual complete regression. To date this has not been achieved and the role of medical treatment in the management of fibroids has been limited. Progestogens
Early reports of the use of progesterone or progestogens, gave varying results. Goodman (1946) treated seven women with intramuscular progesterone in weekly doses varying between 30 and 70mg. He reported decreases in volume varying between 25 and 40% but these estimates were all based on clinical examination. In a study in which uterine size was determined by contrast radiography, Segaloff et al (1949) failed to demonstrate any reduction in the size of fibroids after treatment with higher doses of progesterone, despite induction of endometrial atrophy. Goldzieher et al (1966) reported marked degenerative changes in fibroids after administration of medrogesterone 25 mg daily for 3 weeks prior to hysterectomy although norethisterone 2 mg daily for 30-90 days preoperatively produced
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no change. This is likely to be related to differences in the nature of the two progestogens as well as to the doses given although further studies have not been performed. On the basis of these early studies, progestogens are seldom prescribed for the management of bleeding associated with uterine fibroids.
Prostaglandin synthetase inhibitors There is limited experience of the use of prostaglandin synthetase inhibitors in menorrhagia related to fibroids. One study comparing the use of naproxen with placebo in fibroid-induced menorrhagia and idiopathic menorrhagia showed a 36% reduction in measured blood loss with naproxen (500-1000 mg/day) in the idiopathic group but no consistent effect in the women with fibroids (Ylikorkala and Pekonen, 1986). Pre-treatment blood loss was considerably higher in the group with fibroids.
Oral contraceptives It is not known whether use of the oral contraceptive pill is beneficial in women with fibroid-related menorrhagia. It is commonly stated that the pill is contraindicated in women with fibroids and there has been a report of enlargement during oral contraceptive therapy (John and Martin, 1971) although this has not been described elsewhere and such an effect seems unlikely with current low-dose preparations of the pill. There is evidence that use of the pill may protect against the later development of uterine fibroids (Ross et al, 1986), particularly where the formulation is relatively high in progestogen. There seems to be no reason why, in contemporary gynaecological practice, the pill might not be used in the management of women with small fibroids where contraception is needed or where there is associated menorrhagia. Uterine size can easily be monitored by ultrasound.
Androgens Androgenic steroids may be used to suppress menstruation but there is little experience of their use in menorrhagia associated with fibroids. Danazol is effective in the management of dysfunctional uterine bleeding (Chimbira et al, 1979) but there have been no published reports of significant reduction in the volume of uterine fibroids. Another less well known androgen is gestrinone, a trienic 19-norsteroid. In a large series of 97 women with fibroids (Coutinho et at, 1986), reduction of mean uterine volume by 20% was reported after 4 months of therapy when 7.5-10 mg was given orally each week in divided doses. Vaginal administration was ineffective in reducing uterine volume. Menorrhagia was relieved, with 96% of the women becoming amenorrhoeic after 4 months of treatment. Gestrinone may be of value in the medical management of fibroids although side-effects related to its androgenicity have not been fully evaluated.
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LHRH analogues in the management of uterine fibroids
Analogues of L H R H are derived from the parent compound by substitutions in the decapeptide chain which give increased potency and duration of action. Both agonists and antagonists are available but clinical experience with the agonists is considerably more advanced (see Fraser and Baird, 1987). The rationale for the use of these compounds in the treatment of fibroids is the ovarian suppression which results from their administration. A single dose of an L H R H agonist stimulates gonadotrophin secretion and release (Sandow, 1983), while prolonged administration causes downLU Z
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Figure 4. Inhibition of ovulation and suppression of ovarian follicular activity during 6 m o n t h s therapy with goserelin (Zoladex depot) 3.6 m g every 28 days, starting in the mid-luteal phase of the cycle. Results from 12 w o m e n expressed as the m e a n + SD of urinary steroid metabolites m e a s u r e d twice weekly. Post-treatment results are adjusted around the onset of first menstruation.
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regulation of the pituitary with consequent failure of ovarian follicular development and anovulation (Figure 4). L H R H agonists can be administered by nasal spray, subcutaneous injection or slow-release depot. Two preparations are licensed for use in the UK, namely buserelin nasal spray (Suprefact, Hoechst) and goserelin subcutaneous depot (Zoladex, ICI). The latter is administered from a pre-packed syringe in the form of a biodegradable rod from which the agonist is released at a constant rate over 28 days. Depot administration is more convenient and gives more reproducible piuitary-ovarian suppression than the intranasal route (West and Baird, 1987). There are now a number of published studies which have demonstrated shrinkage of uterine fibroids and relief of menstrual problems during shortterm therapy with various L H R H agonists (see review by West, 1989). Complete amenorrhoea is usual after the initial treatment cycle and a significant rise in haemoglobin concentration, haematocrit and serum iron concentration during therapy has been demonstrated (Friedman et al, 1988). Treatment has been by daily subcutaneous injection (Maheux et al, 1985; Coddington et al, 1986), subcutaneous (West et al, t987) or intramuscular (Van Leusden, 1986) depot or by intranasal spray (Maheux et al, 1987). Ovarian suppression and fibroid shrinkage are greater with the subcutaneous than the intranasal route (Friedman et al, 1987) because of poor absorption of the latter, although successful results have been reported with buserelin nasal spray given at a dose of 400 Ixg three times daily (Maheux et al, 1987). Maheux initiated treatment with subcutaneous injections for the first 2 weeks of treatment to achieve more rapid pituitary desensitization. Unfortunately, regardless of the route of administration, shrinkage of the fibroids is rarely complete and is not sustained after cessation of therapy. Reduction of uterine volume by approximately 55% after 6 months therapy has been reported by several different groups (see West, 1989). The greatest reduction in volume appears to occur in the first three months and the fall flattens off thereafter (Figure 5). As yet it is not known whether prolonged 600-
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Figure 5. Reductionof uterine volume(mean +_SD) measuredby ultrasound during 6 months therapy with goserelin depot 3.6 mg every 28 days. Resultsfrom 12 womenshowingmaximal reduction during the initial 3 months, with little change thereafter. The post-treatment measurement was taken 3 months after administration of depot 6.
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therapy would lead to permanent fibroid regression. If such agents are to be an alternative to surgery, therapy is therefore potentially long term. This carries possible consequences of a prolonged hypoestrogenic state, particularly vasomotor side-effects, atrophic vaginitis and bone mineral loss. Many women will be happy to tolerate the side-effects, when compared to their menstrual symptoms but bone loss (Matta et al, 1988) is potentially more serious and is the single factor preventing the widespread use of L H R H agonists in women with fibroids. Nevertheless, these agents offer an alternative to surgery for women who have medical contraindications to surgery for example cardiovascular disease or obesity. They may also be useful for symptomatic women approaching the age of the natural menopause where ovarian suppression is less of a problem and surgery may be difficult to justify on cost-benefit terms.
Future role of LHRH agonists in the management of fibroids There are ways in which the adverse effects of L H R H agonists may be overcome in the future. Many women treated with L H R H agonists show incomplete ovarian suppression, even with depot administration (Figure 6). If, as in the example shown, fibroid volume remains stable, partial ovarian suppression with L H R H agonists administered intranasally or by low-dose depot may be suitable for maintenance therapy provided that symptoms are controlled. In practice this may lead to irregular bleeding and a risk of unopposed oestrogen stimulation of the endometrium (Schmidt-Gollwitzer et al, 1981) so that low-dose cyclical gestogens would be needed to maintain 160-
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regular endometrial shedding. Such therapy has yet to be evaluated in the treatment of fibroids and associated menorrhagia. An alternative strategy would be to abolish ovarian activity with an agonist of L H R H and then to add another agent with the object of enhancing shrinkage of the fibroids while preserving bone mineralization and minimizing vasomotor and other side-effects. Progestogens should fulfill these criteria but our results and those of Friedman et al (1988) have indicated that addition of medroxyprogesterone acetate (MPA) 15-20 mg daily from the start of therapy prevents the initial rapid fibroid shrinkage seen with the L H R H agonist alone. The mechanism of this effect is not clear. These results do not exclude the possibility that addition of MPA at a later stage of therapy may be of value in maintenance of response as MPA does reduce the frequency of hot flushes while maintaining menstrual suppression. Addition of the anti-oestrogen tamoxifen should theoretically enhance fibroid shrinkage by blocking the effects of residual circulating oestrogen. However when given in combination from the start of therapy, tamoxifen also prevents fibroid shrinkage even though pituitary--ovarian suppression is enhanced (Lumsden et al, 1989b). These results suggest that tamoxifen paradoxically has oestrogen agonist actions in women rendered hypooestrogenic with L H R H agonists. If the object of therapy is symptomatic control rather than complete fibroid regression, an alternative approach is the use of low-dose hormone replacement therapy in combination with an L H R H agonist depot. Preliminary experience in 10 premenopausal women treated with goserelin with the addition of cyclical sequential low dose Premarin (0.3 mg) and Provera after three months (Maheux et al, 1988) has shown that fibroid volume appears to remain stable with good control of symptoms. Although promising, this and other similar approaches to the management of fibroids require further evaluation in larger numbers of women before they can be regarded as a true alternative to surgery. L H R H agonists as a preoperative adjunct to surgery
There are a number of ways in which agonists of L H R H may be a valuable adjunct to surgery in women with large and symptomatic uterine fibroids. Arrest of menorrhagia and correction of anaemia will improve the clinical state of the patient and may avoid transfusion. Reduction of the size of the uterus may improve surgical access and enable the use of a more cosmetic surgical incision. It may, in some cases, enable vaginal rather than abdominal hysterectomy to be performed. During therapy with an L H R H agonist, a reduction of bloodflow through the uterine arteries and through the major arteries supplying individual fibroids has been demonstrated using Doppler ultrasound (Matta et al, 1988) and this reduced vascularity may be associated with a reduction in operative blood loss. In a pilot study of 13 women pre-treated for 3 months with goserelin, compared with 14 untreated controls, blood loss at hysterectomy was significantly lower in the treated women (Lumsden et al, 1987). In addition, postoperative pyrexia was less frequent in the treated group. We are currently conducting a larger,
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placebo-controlled, randomized, multicentre study to assess the value of L H R H agonist therapy prior to hysterectomy. There is also the possibility that preoperative treatment with L H R H agonists will be useful in women undergoing conventional myomectomy or hysteroscopic resection of submucous fibroids. Myomectomy is frequently complicated by haemorrhage and there is a high rate of postoperative adhesions (Bonney, 1931; Rubin IC, 1942), presumably related to oozing from surgical incisions and this has an adverse effect on later fertility. Current experience of the use of L H R H agonists prior to myomectomy is limited. In a small personal series, Shaw (1989) reported a significant reduction in operative blood loss but more difficulty in enucleation of the fibroids following pretreatment with L H R H agonist. Clearly there is a need for multicentre evaluation of this approach, particularly in relation to longterm results. SUMMARY
Fibroids are an important cause of menorrhagia, resistant to conventional methods of medical treatment. The mechanism of their effect on menstrual blood loss is poorly understood but may involve abnormalities of local venous drainage, enlargement of the uterine cavity and abnormalities in prostaglandin production. Their cause remains unknown although it has long been assumed that they are oestrogen-dependent. In the past, study of their aetiology, prevention and treatment has received scant attention. Recent developments including measurement of tissue receptors for steroids and growth factors, non-invasive methods of monitoring fibroid growth and the use of L H R H agonists have enabled further study of their nature and of their response to therapy although much work remains to be done. The majority of women with uterine fibroids associated with menorrhagia are treated by hysterectomy although developments in endoscopic surgery have enabled a more conservative approach in some circumstances. L H R H agonists are the only medical agents which cause substantial shrinkage of fibroids although regression is not permanent. These agents are of value in short-term relief of symptoms and are likely to be a useful adjunct to surgery by reducing both uterine volume and bloodflow. However, because of the consequences of prolonged ovarian suppression, they are not suitable for long-term use unless there are medical contraindications to surgery. It remains to be seen whether their use in low-dose regimens or in combination with other agents will provide a successful, safe and cost-effective alternative to hysterectomy in women whose primary problem is heavy menstrual loss. They do however offer a means of conserving reproductive function in women wishing to retain this option. REFERENCES Aharoni A, Reiter A, Golan D, Paltiely Y & Sharf M (1988) Patterns of growth of uterine leiomymomas during pregnancy. A prospective longitudinal study. British Journal of Obstetrics and Gynaecology 95: 510-514.
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Bonney V (1931) The technique and results of myomectomy. Lancet i: 171-177. Buttram VC & Reiter RC (1981) Uterine leiomyomata: etiology, symptomatology and management. Fertility and Sterility 36: 433-445. Chegini N, Rao CV, Wakim N & Sanfilippo J (1986) Binding of 125I-epidermal growth factor in human uterus. Cell and Tissue Research 246: 543-548. Chimbira TH, Cope E, Anderson ABM & Bolton FG (1979) The effect of danazol on menorrhagia, coagulation mechanisms, haematological indices and body weight. British Journal of Obstetrics and Gynaecology 86: 46-50. Cochrane WJ & Thomas MA (1974) Ultrasound diagnosis of gynecologic pelvic masses. Radiology 110: 649-654. Coddington CC, Collins RL, Shawker TH et al (1986) Long-acting gonadotrophin hormonereleasing hormone analog used to treat uteri. Fertility and Sterility 45: 624-629. Corscaden JA & Singh BP (1958) Leiomyosarcoma of the uterus. American Journal of Obstetrics and Gynecology 75: 149-153. Coutinho EM, Boulanger GA & Goncalves MT (1986) Regression of uterine leiomyomas after treatment with gestrinone, an antiestrogen, antiprogesterone. American Journal of Obstetrics and Gynecology 155: 761-767. Davis J (1987) The principles and use of the neodymium-YAG laser in gynaecological surgery. Balliere's Clinical Obstetrics and Gynaecology 1: 331-352. Deligdish L & Loewenthal M (1970) Endometrial changes associated with myomata of the uterus. Journal of Clinical Pathology 23: 676-680. Dickson RB, H u f K-K, Spencer EM & Lippman ME (1986) Induction of epidermal growth factor-related polypeptides by 17J3-estradiol in MCF-7 human breast cancer cells. Endocrinology 118: 138-142. Farber M, Conrad S, Heinrichs W & Herrmann W (1972) Estradiol binding by fibroid tumours and normal myometrium. Obstetrics and Gynecology 40: 479-486. Farrer-Brown G, Beilby JOW & Tarbit MH (1971) Venous changes in the endometrium of myomatous uteri. Obstetrics and Gynecology 38: 743-751. Filicori M, Hall DA, Loughtin JS et al (1983) A conservative approach to the management of uterine leiomyomata: pituitary desensitisation by a luteinizing hormone-releasing hormone analogue. American Journal of Obstetrics and Gynecology 147: 726-727. Fraser HM & Baird DT (1987) Clinical applications of LHRH analogues. Balliere's Clinical Endocrinology and Metabolism 1: 43-70. Friedman AJ, Barbieri RL, Benacerraf BR & Schiff I (1987) Treatment of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin-releasing hormone agonist. Fertility and Sterility 48: 560-564. Friedman A J, Barbieri RL, Doubilet PM, Fine C & Schiff I (1988) A randomised double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertility and Sterility 49: 404--409. Goldrath MH, Fuller TA & Segal S (1981) Laser photovaporisation of the endometrium for the treatment of menorrhagia. American Journal of Obstetrics and Gynecology 140: 14-19. Goldzieher JW, Maqueo M, Ricard L, Aguilar JA & Canales E (1966) Induction of degenerative changes in uterine myomas by high dose progestin therapy. American Journal of Obstetrics and Gynecology 96: 1078-1087. Gonzalez F, Lakshmanan J, Hoath S & Fisher DA (1984) Effect of estradiol-1713 on uterine epidermal growth factor concentration in immature mice. Acta Endocrinologica 105: 425-428. Goodman AL (1946) Progesterone therapy in uterine fibromyomata. Journal of Clinical Endocrinology and Metabolism 6: 402-408. Hallez JP, Netter A & Cartier R (1987) Methodical intrauterine resection. American Journalof Obstetrics and Gynecology 156: 1080-1084. Hannigan EV & Gomez LG (1979) Uterine leiomyosareoma: a review of prognostic clinical and pathological features. American Journal of Obstetrics and Gynecology 134: 557-564. Healy DL, Lawson SR, Abbott M, Baird DT & Fraser HM (1986) Towards removing uterine flbroids without surgery: subcutaneous infusion of a luteinizing hormone-releasing hormone agonist commencing in the luteal phase. Journal of Clinical Endocrinology and Metabolism 63: 619-625. Hofman GE, Rao CHV, Barrows GH, Rossano LT & Sanfilippo JS (1984a) Prostaglandin E
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and F2~ receptors in human uterine leiomyomas. Journal of Clinical Endocrinology and Metabolism 58: 880-884. Hofman GE, Rao CHV, Barrows GH, Schutz GS & Sanfilippo JS (1984b) Binding sites for epidermal growth factor in human uterine tissue and leiomyomas. Journal of Clinical Endocrinology and Metabolism 58: 880-884. Hricak H, Lacey C, Schriock E et al (1985) Gynecologic masses: value of magnetic resonance imaging. American Journal of Obstetrics and Gynecology 153: 31-37. Iosif CS & Akerlund M (1983) Fibromyomas and uterine activity. Acta Obstetrica and Gynecologica Scandanavica 62" 165-167. John AH & Martin R (1971) Growth of leiomyomata with oestrogen-progesterone therapy. Journal of Reproductive Medicine 6: 56--58. Lawson TL ~Albarelli JN (1977) Diagnosis of gynecologic pelvic masses by gray scale ultrasonography: analysis of specificity and accuracy. American Journal of Roentgenology 128: 1003-1006. Lee NC, Dicker RC, Rubin GL & Ory HW (1984) Confirmation of the preoperative diagnoses for hysterectomy. American Journal of Obstetrics and Gynecology 150: 283-287. Lipschutz A (1942) Experimental fibroids and the antifibromatogenic action of steroid hormones. Journal of the American Medical Association 120: 171-174. Lomano JM (1986) Photocoagulation of the endometrium with the Nd:YAG laser for the treatment of menorrhagia. Journal of Reproductive Medicine 31: 148-150. Lumsden MA, Kelly RW & Baird DT (1983) Is prostaglandin F~, involved in the increased myometrial contractility of primary dysmenorrhoea? Prostaglandins 25: 683-692. Lumsden MA, West CP & Baird DT (1987) Goserelin therapy before surgery for uterine fibroids. Lancet i: 36--37. Lumsden MA, West CP, Bramley T, Rumgay L & Baird DT (1988) The binding of EGF to the human uterus and leiomyomata in women rendered hypo-oestrogenic by continuous administration of a LHRH agonist. British Journal of Obstetrics and Gynaecology 95: 1299-1304. Lumsden MA, West CP, Hawkins TA, Rumgay L & Baird DT (1989a) The binding of steroids to myometrium and leiomyomata in women treated with the gonadotrophin-releasing hormone agonist, Zoladex (ICI 118630). Journal of Endocrinology 121: 389-396. Lumsden MA, West CP, Hillier H & Baird DT (1989b) Tamoxifen acts as an oestrogen agonist in women treated with LHRH agonists (Zoladex) and prevents shrinkage of uterine fibroids. Fertility and Sterility (in press). Maheux R, Guilloteau C, Lemay A, Bastide A & Fazekas ATA (1985) Luteinizing hormonereleasing hormone agonist and uterine leiomyoma: a pilot study. American Journal of Obstetrics and Gynecology 152: 1034-1039. Maheux R, Lemay-Turcot L & Lemay A (1986) Daily follicle-stimulatinghormone, luteinizing hormone, estradiol and progesterone in ten women harboring uterine leiomyomas. Fertility and Sterility 46: 205-208. Maheux R, Lemay A & Merat P (1987) Use of intranasal luteinizing hormone-releasing hormone agonist in uterine leiomyomas. Fertility and Sterility 47- 229-233. Maheux R, Lemay A, Blanchet P, Fontaine JY & Faure N (1989) An alternative to hysterectomy in premenopausal women harboring leiomyomata: combined utilisation of LHRH agonist and hormone replacement therapy. International Symposium on Endocrine therapy, Monaco, November 1988, proceedings to be published. Matta WH, Shaw RW, Hesp R & Katz D (1987) Hypogonadism induced by luteinizing hormone releasing hormone analogues: effects on bone density in premenopausal women. British Medical Journal 294: 1523-1524. Matta MHM, Stabile, I, Shaw RW & Campbell S (1988) Doppler assessment of uterine blood flow changes in patients with fibroids receiving the gonadotropin-releasing hormone agonist buserelin. Fertility and Sterility 49: 1083-1085. Miller NF & Ludovici PP (1955) On the origin and development of uterine fibroids. American Journal of Obstetrics and Gynecology 70: 720-739. Miller NF, Ludovici PP & Dontas E (1953) The problem of the uterine fibroid. American Journal of Obstetrics and Gynecology 66: 734-746. Mukku VR & Stancel GM (1985) Regulation of epidermal growth factor receptor by estrogen. Journal of Biological Chemistry 260: 9820-9824. Murphy AA (i987) Operative laparoscopyl Fertility and Sterility 47: 1-18.
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Pickles VR, Hall WJ, Best FA & Smith GN (1965) Prostaglandins in endometrium and menstrual fluid from normal and dysmenorrhoeic subjects. British Journal of Obstetrics and Gynaecology 72: 185-192. Pollow K, Geilfuss J, Boquoi E & Pollow B (1978) Estrogen and progesterone binding protein in normal human myometrium and leiomyoma tissue. Journal of Clinical Chemistry and Clinical Biochemistry 16: 503. Puuka MJ, Kontula KK, Kauppila AJ, Janne OA & Vihko RK (1976) Estrogen receptor in human myoma tissue. Molecular and Cellular Endocrinology 6: 35--44. Randall JH & Odell LD (1943) Fibroids in pregnancy. American Journal of Obstetrics and Gynecology 46: 349--357. Rees MCP & Turnbull A (1985) Leiomymomas release prostaglandins. Prostaglandins, Leukotrines and Medicine 18: 65-68. Richards DH (1973) Depression after hysterectomy. Lancet ii: 430-433. Ross RK, Pike MC, Vessey MP et al (1986) Risk factors for uterine flbroids: reduced risk associated with oral contraceptives. British Medical Journal 293: 359-362. Rubin A & Ford JA (1974) Uterine fibromyomata in urban blacks. South African Medical Journal 48: 2060. Rubin IC (1942) Progress in myomectomy: surgical measures and diagnostic aids favoring lower morbidity and mortality. American Journal of Obstetrics and Gynecology 44: 196-212. Rybo G, Leman J & Tibblin R (1985) Epidemiology of menstrual blood loss. In Baird DT & Michie EA (eds) Mechanisms of menstrual bleeding, pp 181-193. New York: Raven Press. Sandow J (1983) Clinical applications of LHRH and its analogues. ClinicalEndocrinology 18: 571-592. Sampson JA (1913) The influence of myomata on the blood supply'of the uterus with special reference to abnormal uterine bleeding. Surgery Gynecology and Obstetrics 16: 144-180. Schmidt-Gollwitzer M, Hardt W, Schmidt-Gotlwitzer K, vonder Ohe M & Nevinny-Stickel J (1981) Influence of the LH-RH analogue buserelin on cyclic ovarian function and on endometrium. A new approach to fertility control? Contraception 23: 187-195. Sciarra JJ & Valle RF (1977) Hysteroseopy: A clinical experience with 320 patients. American Journal of Obstetrics and Gynecology 127: 340-348. Scottish Hospital In-Patient Statistics (1985) Information Services Division, Scottish Health Service Common Services Agency. Segaloff A, Weed JC, Sternberg WH & Parson W (1949) The progesterone therapy of human uterine leiomyomas. Journal of Clinical Endocrinology and Metabolism 9: 1273-1291. Shaw RW (1989) Data presented at International Symposium on Endocrine Therapy, Monaco, November 1988, proceedings to be published. Sheets EE, Tsibris JCM, Cook NI et al (1985) In vitro binding of insulin and epidermal growth factor to human endometrium and endocervix. American Journal of Obstetrics and Gynecology 153: 60-65. Smith CJ (1952) Hysterectomy for benign pelvic conditions. American Journal of Obstetrics and Gynecology 64: 1211-1220. Smith SK, Abel MH, Kelly RW & Baird DT (1981a) Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. British Journal of Obstetrics and Gynaecotogy 88: 434-442. Smith SK, Kelly RW, Abet MH & Baird DT (1981b) A role for prostaeyclin in excessive menstrual bleeding. Lancet i: 522-524. Spellacy WN, LeMaire WJ, Buhl WC, Birk SA & Bradley BA (1972) Plasma growth hormone and estradiol levels in women with uterine myomas. Obstetrics and Gynecology 40: 829-834. Staros JV, Cohen S & Russo RW (i985) Epidermal growth factor receptor: characterisation of its protein kinase activity. In Cohen P and Houslay M (eds) Molecular Mechanisms of Transmembrane Signalling, pp 253--277. Elsevier Science Publishers. Thornton WN & Carter JP (1951) Sarcoma of the uterus, a clinical study. American Journal of Obstetrics and Gynecology 62: 294-301. van Leusden H (1986) Rapid reduction of uterine myomas after short-term treatment with microencapsulated D-Trp6-LHRH. Lancet ii: 1213. West CP (1989) LHRH analogues in the management of uterine fibroids, premenstrual
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syndrome and breast malignancies. Balliere's Clinical Obstetrics and Gynaecology 2: 689-709. West CP & Baird DT (1987) Suppression of ovarian activity by Zoladex depot (ICI 118630), a long-acting luteinizing hormone releasing hormone agonist analogue. Clinical Endocrinology 26: 213-220. West CP, Lumsden MA, Lawson S, WiUiamson J & Baird DT (1987) Shrinkage of uterine fibroids during therapy with goserelin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot. Fertility and Sterility 48: 45-51. Wilson EA, Yang F & Rees ED (1980) Estradiol and progesterone binding in uterine leiomyomata and in normal uterine tissues. Obstetrics and Gynecology 55: 20-24. Witherspoon JT (1935) The hormonal origin of uterine fibroids: a hypothesis. American Journal of Cancer 24: 402-406. Witherspoon JT & Butler VW (1934) The etiology of uterine fibroids with specific reference to the frequency of their occurrence in the negro: a hypothesis. Surgery Obstetrics and Gynecology 58: 57-61. Ylikorkala O & Pekonen F (1986) Naproxen reduces idiopathic but not fibromyomata-induced menorrhagia. Obstetrics and Gynecology 68: 10-12.
Uterine fibroids, also known as leiomyomata, are common benign tumours which arise in the myometrium. They are composed predominantly of smooth muscle with a variable amount of connective tissue and have a characteristic smooth white whorled appearance when cross-sectioned. Three subtypes are recognized depending on their situation in relation to the uterine wall, namely submucous, subserous and intramural. They are commonly multiple and may result in considerable uterine enlargement (Figure 1). Leiomyomata are found in postpubertal women of all ages but are most commonly seen towards the end of reproductive life. It has been estimated that between 20 and 25% of women over the age of 35 years have fibroids (Smith C J, 1952). Fibroids are frequently asymptomatic but may be associated with infertility and pregnancy loss. The mechanism of their effect on fertility is uncertain but mechanical factors are likely to play a part through cornual
Figure 1, Multiple fibroids causing gross uterine enlargement. Hysterectomy specimen. BaiUiOre's Clinical Obstetrics and Gynaecology--Vol. 3, No. 2, June 1989
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obstruction and interference with implantation. It has been stated that fibroids are a consequence rather than a cause of childlessness (Witherspoon, 1935). Nevertheless, in women desiring pregnancy, a conception rate of 40% following myomectomy has been quoted (Buttram and Reiter, 1981). Menstrual upset (see below) is commonly attributed to the presence of fibroids and pressure effects from large tumours are frequently reported. Although they may be associated with dysmenorrhoea, fibroids are usually painless unless they undergo torsion or degeneration. FIBROIDS AND MENORRHAGIA
Fibroids are a well recognized cause of menorrhagia although the proportion associated with excessive menstrual loss is not well documented. In the above quoted review of women undergoing myomectomy (Buttram and Reiter, 1981), 30% of the women complained of menorrhagia although the proportion varied from 17 to 61% in nine individual series. In one study fibroids were diagnosed in only 10% of women complaining of menorrhagia whose measured blood loss was between 80 and 100 ml but in as many as 40% of those with measured blood loss in excess of 200 ml (Rybo et al, 1985). Nevertheless, the association between fibroids and menorrhagia has been challenged, Miller et al (1953) attributing this symptom only to the presence of submucous fibroids. The latter, however, accounted for only a quarter of cases of menorrhagia is one South African series of women with fibroids (Rubin A and Ford, 1974) and it now seems clear that heavy menstrual loss may be associated with uterine fibroids in any site. Mechanism of abnormal bleeding
The mechanism of abnormal bleeding in the presence of uterine fibroids is unknown. In the past, most cases of abnormal menstruation associated with fibroids were attributed to abnormalities of ovarian function (Miller and Ludovici, 1955), rather than to the presence of the fibroids. A reported association between uterine fibroids and hyperplastic changes in the endometrium (Deligdish and Loewenthal, 1970) has been used as more recent evidence to support a common mechanism in the aetiology of the two conditions although the same authors also described atrophic changes in endometrium from the same subjects. This mixed histological picture has been reported by others (Farrer-Brown et al, 1971) and is more likely to reflect local differences in steroid binding within the uterus rather than abnormal ovarian function. Endocrine investigation has failed to identify any abnormality of circulating ovarian steroids in women with fibroids (Spellacy et al, 1972; Maheux et al, 1986), compared with normal controls. The origin of heavy menstrual loss has been regarded as secondary to enlargement of the surface area of the uterine cavity or due to necrosis of the endometrium overlying submucous fibroids. The latter was disputed in an early study by Sampson (1913) who attributed the excessive blood loss to the presence of dilated venous plexuses in the myometrium and endometrium
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adjacent to myomata. His results were confirmed by Farrer-Brown et al (1971) who performed histological and microradiographic studies on hysterectomy specimens. Dilated endometrial and myometrial veins were a consistent finding, seen not only in proximity to individual fibroids but also some distance away and were thought to be obstructive in origin. Venous dilatation was most marked in relation to large submucous fibroids but was also present with intramural and some subserous fibroids. These dilated endometrial veins are likely to be involved in the pathogenesis of heavy menstrual loss and might explain the association of menorrhagia with intramural and subserous fibroids as well as those encroaching directly upon the uterine cavity. Abnormalities in prostaglandin production from the uterus have been implicated in both dysfunctional uterine bleeding (Smith SK et al, 1981a,b) and dysmenorrhoea (Pickles et al, 1965; Lumsden et al, 1983). Fibroids have been shown to release prostaglandins in vitro (Rees and Turnbull, 1985), the principal prostaglandin produced being 6-keto PGF1, the stable metabolite of prostacyclin. Since this is a potent vasodilator, it may contribute to the menorrhagia associated with the presence of fibroids. It has also been suggested that menstrual abnormalities related to fibroids are due to a disturbance in normal myometrial contractility (Farrer-Brown et al, 1971). Intrauterine pressure recordings made in women with fibroids prior to hysterectomy have demonstrated abnormalities of uterine activity (Iosif and Akerlund, 1983). This may reflect differences in the proportions of smooth muscle and connective tissue in fibroids compared to normal myometrium. It may also be associated with a decreased number of prostaglandin receptors in fibroids compared with surrounding myometrium (Hofmann et al, 1984a). Prostaglandins are potent stimulators of smooth muscle contractility and these differences may result in inco-ordinate smooth muscle activity. AETIOLOGY Uterine leiomyomata are thought to be oestrogen-dependent since they do not occur prior to puberty and they become smaller after the menopause. Recent studies have demonstrated a significant reduction in fibroid size in women rendered hypo-oestrogenic with agonists of luteinizing hormone releasing hormone (LHRH) (Filicori et al, 1983; West et al, 1987). Conversely, however, there is little evidence that excessive stimulation with oestrogen promotes growth of fibroids. Two studies have failed to demonstrate enlargement of fibroids during pregnancy (Randall and Odell, 1943; Aharoni et al, 1988), contrary to common belief. Similarly, although an association between fibroids, anovular cycles and endometrial hyperplasia has been described (Witherspoon and Butler, 1934), recent studies have shown no difference in ovarian activity between women with fibroids and a control group (see above). Evidence for the oestrogen stimulation theory was based on experimental work on guinea pigs given prolonged oestrogen therapy (Lipschutz, 1942).
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Benign uterine and extragenital tumours were observed and found to be inhibited by progesterone or testosterone. However critics of these experiments have pointed out that these tumours were composed of connective tissue rather than of smooth muscle (Segaloff et al, 1949) and thus differ from true leiomyomas. Fibroids are not seen in animal species and thus there is no appropriate animal model for study. Research into their nature and causation must therefore be based on human material. Oestrogen acts via receptors in the membranes of responsive cells and recent study of its mechanism of action has centred on these. Steroid receptors have been demonstrated in both myometrium and fibroid (Farber et al, 1972; Puuka et al, 1976; Wilson et al, 1980) and some workers suggest that the concentration of binding sites is greater in fibroids (Farber et al, 1972, Wilson et al, 1980). In order to elucidate the mechanism whereby oestrogen influences the growth of fibroids, we have studied the effect of the oestrogen suppression associated with L H R H agonist therapy on oestrogen receptors in fibroid and myometrium. Women with fibroids who were scheduled for hysterectomy were pre-treated for 3 months with goserelin (Zoladex), an agonist of L H R H which is administered as a monthly subcutaneous depot and which produces consistent oestrogen suppression (West and Baird, 1987). Binding of steroids to these uteri was compared with those from women with fibroids who had received no therapy prior to surgery. The receptor concentration was measured using the separation of bound from free hormone with dextran-coated charcoal which assesses unoccupied receptors and an enzyme immunoassay which is thought to measure the total number of receptors (Lumsden et al, 1989a). We confirmed the results of Wilson et al (1980) by demonstrating higher concentration of oestrogen receptors in fibroids than in the surrounding myometrium (Lumsden et al, 1989a) but we also found that both unoccupied and total receptor concentrations rose with the use of L H R H agonists (Figure 2). This was an unexpected result since the concentration of oestradiol receptors in tissues is thought to be proportional to the levels of circulating oestradiol and the latter is low in Oestradiol
EGF
120
30
100 80
20
~ 6o
E
40
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20 0 Fibroid
Myometrium Tissue
Fibroid
Myometrium
Tissue
Figure 2. Specific binding of oestradiol and epidermal growth factor to uterine tissue homogenates following 3 months treatment with goserelin (n = 12), compared with untreated controis (n --- 12). Data are median values. For details see published papers by Lumsden et al.
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agonist treated women. As the size of the uterine fibroids was reduced by the L H R H agonist, a decrease in receptor number might have been expected in the treated women. Both unoccupied and total receptor concentrations were increased so that the results cannot be explained simply by the low concentration of circulating oestradiol. This suggests that the rise is due to an actual increase in receptor concentration and makes a direct action of oestradiol on the tissues unlikely. It is possible that oestrogen exerts an effect on fibroid growth via another factor. Epidermal growth factor (EGF) is a member of the group of peptide hormones which control the rate and extent of cell proliferation. The addition of EGF to cell cultures induces many cellular responses including morphological changes, stimulation of various active transport systems for both inorganic ions and low molecular weight metabolites, phosphoinositol turnover and the formation of macromolecules including RNA, protein and D N A (for review see Staros et al, 1985). High affinity binding sites have been demonstrated in the human uterus (Hofman et al, 1984b; Sheets et al, 1985) and in the rat uterus (Mukku and Stancel, 1985). In the rat, the binding of EGF to the uterus is regulated by oestrogen (Mukku and Stancel, 1985). Oestradiol also increases the EGF content of mouse uterus (Gonzalez et al, 1984). Oestrogen has been shown to induce the production of EGF-related polypeptides from a breast cancer cell line (Dickson et al, 1986). EGF binds to all the cell types in the human uterus but no changes have been observed during the menstrual cycle (Chegini et al, 1986). In the hysterectomy specimens described above, we found that pre-treatment with an L H R H agonist significantly decreased the concentration of binding sites for EGF in fibroid tissue but not in the surrounding myometrium (Figure 2; Lumsden et al, 1988). It is thus possible that oestradiol exerts its action on fibroid growth via an alteration of the binding of epidermal growth factor. INVESTIGATIONS Uterine fibroids are usually diagnosed clinically but there are a number of techniques which are of value in further assessment. Pelvic ultrasound (Figure 3) is now routinely performed to evaluate the nature of large masses, particularly to differentiate uterine enlargement from an ovarian lesion and to exclude pregnancy. Studies comparing ultrasound appearances with the histological nature of a pelvic tumour removed surgically have shown ultrasound to be accurate in over 80% of cases (Cochrane and Thomas, 1974; Lawson and Albarelli, 1977). The commonest source of confusion is between pedunculated subserous fibroids and solid ovarian tumours. Magnetic resonance imaging (Hricak et al, 1985) is a more accurate method of diagnosis of pelvic tumours but is expensive and less widely available. If any doubt remains about the nature of a pelvic tumour, laparoscopy or laparotomy are indicated. As well as their value for diagnostic purposes, the techniques mentioned above are valuable for serial monitoring of fibroid size during conservative management or in assessing the response to medical therapy (see below).
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Using ultrasound, the volume of spherical tumours can easily be calculated by applying the formula 4/3-r:r3 to individual fibroids or to the whole uterus (Healy et al, 1986; West et al, 1987). The accuracy of this technique has been validated by comparison of uterine volume measured by ultrasound one day prior to hysterectomy with the volume of the fresh operative specimen measured by water displacement. A highly significant correlation between the two sets of measurements was found (Lumsden et al, 1987). We found the technique to be accurate even in cases where the uterine outline was irregular. Menstrual abnormalities cannot always be assumed to be attributable to the presence of fibroids, particularly if there are disturbances in the normal
Figure 3.
Ultrasound m e a s u r e m e n t of fibroid uterus.
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cycle pattern in women over the age of 40 years. Curettage or endometrial biopsy is always indicated in these circumstances. Hysterosalpingography and hysteroscopy (Sciarra and Valle, 1977) may be helpful in the detection of submucous fibroids but are used more often in the evaluation of infertility or recurrent abortion than in the investigation of menorrhagia. As newer forms of treatment of fibroids gain popularity, accurate diagnosis with the aid of these methods may become more relevant. MANAGEMENT The management of women with uterine fibroids depends on the associated symptoms, the age and the reproductive status of the individual. Small asymptomatic fibroids rarely require intervention, provided that their nature is certain. There has been a tendency in the past to treat large fibroids surgically even when they are asymptomatic, because of possible confusion with ovarian neoplasia. This problem has been largely overcome in contemporary gynaecological practice because of the wide availability of diagnostic ultrasound (see above). Surgical treatment has also been favoured because of the theoretical risk of sarcomatous change in a fibroid. It is thought, however, that the risks have been overemphasized and that the true incidence is below 0.2% (Corscaden and Singh, 1958). Sarcomas usually give rise to pain, abnormal bleeding and sometimes systemic upset. They occur most frequently in postmenopausal women (Thornton and Carter, 1951; Hannigan and Gomez, 1979) and uterine enlargement and onset of symptoms in this age group would certainly warrant surgical intervention. Otherwise, asymptomatic fibroids can be managed conservatively, provided that adequate facilities exist for assessment and monitoring. Surgical treatment The treatment of women with fibroids associated with menorrhagia is conventionally by hysterectomy. The presence of fibroids is one of the commonest indications for hysterectomy, comprising 30% of all indications in the United States (Lee et al, 1984). In Scotland in 1985, 21% of hysterectomies were for fibroids, taking up a total of 16722 bed days with an average stay of 8.9 days (Scottish Hospital In-Patient Statistics, 1985). Conservative surgery by myomectomy is usually reserved for women desiring fertility, although many of this group may also be troubled by heavy menstruation. Of the two procedures, myomectomy carries a higher morbidity than hysterectomy and may be technically more difficult. Myomectomy in women with menorrhagia has been followed by subjective relief of this symptom in between 40 and 91% of cases (Buttram and Reiter, 1981). However further surgery is estimated to be necessary in 10% of women treated initially by myomectomy for various indications. If hysterectomy is required at a later date, it may be rendered more difficult by previous myomectomy because of the high incidence of postoperative adhesions (Rubin IC, 1942).
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Newer surgical methods
Direct visualization of subserous and intramural fibroids by laparoscopy and of submucous fibroids by hysteroscopy (Sciarra and Valle, 1977) has made the endoscopic treatment of small fibroids possible in certain circumstances. Both pedunculated and intramural fibroids may be removed laparoscopically with the aid of eleetrocoagulation (Murphy, 1987), although this technique is unlikely to be relevant to the management of women with menorrhagia. Submucous fibroids may be removed vaginally if prolapsed or resected under hysteroscopic visualization using an electrical loop (Hallez et al, 1987) although use of the hysteroscope is less popular in the United Kingdom than in the United States. There have been a few reports of the successful use of ablation or coagulation of the endometrium with the neodymium-yttrium aluminium garnet (Nd-YAG) laser in women with menorrhagia (Goldrath et al, 1981; Lomano, 1986) and this technique may be applicable to small submucous fibroids. However the procedure is timeconsuming, technically difficult to master (Davis, 1987) and currently of limited availability (see Chapter 12). Medical treatment of uterine fibroids
There is considerable demand for an alternative to surgery in the management of uterine fibroids. This is not confined to women desiring pregnancy. Many women have serious objections to hysterectomy and this is important in certain racial groups where the prevalence of fibroids may be particularly high (Witherspoon and Butler, 1934). Psychological sequelae of hysterectomy, although uncommon, are well documented (Richards, 1973) and there is well recognized surgical morbidity. There are also important economic considerations as more women assume positions of responsibility within society and in families where the woman is the major breadwinner. Ideally, medical therapy should control symptoms and cause shrinkage and degeneration of the fibroids, leading to their eventual complete regression. To date this has not been achieved and the role of medical treatment in the management of fibroids has been limited. Progestogens
Early reports of the use of progesterone or progestogens, gave varying results. Goodman (1946) treated seven women with intramuscular progesterone in weekly doses varying between 30 and 70mg. He reported decreases in volume varying between 25 and 40% but these estimates were all based on clinical examination. In a study in which uterine size was determined by contrast radiography, Segaloff et al (1949) failed to demonstrate any reduction in the size of fibroids after treatment with higher doses of progesterone, despite induction of endometrial atrophy. Goldzieher et al (1966) reported marked degenerative changes in fibroids after administration of medrogesterone 25 mg daily for 3 weeks prior to hysterectomy although norethisterone 2 mg daily for 30-90 days preoperatively produced
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no change. This is likely to be related to differences in the nature of the two progestogens as well as to the doses given although further studies have not been performed. On the basis of these early studies, progestogens are seldom prescribed for the management of bleeding associated with uterine fibroids.
Prostaglandin synthetase inhibitors There is limited experience of the use of prostaglandin synthetase inhibitors in menorrhagia related to fibroids. One study comparing the use of naproxen with placebo in fibroid-induced menorrhagia and idiopathic menorrhagia showed a 36% reduction in measured blood loss with naproxen (500-1000 mg/day) in the idiopathic group but no consistent effect in the women with fibroids (Ylikorkala and Pekonen, 1986). Pre-treatment blood loss was considerably higher in the group with fibroids.
Oral contraceptives It is not known whether use of the oral contraceptive pill is beneficial in women with fibroid-related menorrhagia. It is commonly stated that the pill is contraindicated in women with fibroids and there has been a report of enlargement during oral contraceptive therapy (John and Martin, 1971) although this has not been described elsewhere and such an effect seems unlikely with current low-dose preparations of the pill. There is evidence that use of the pill may protect against the later development of uterine fibroids (Ross et al, 1986), particularly where the formulation is relatively high in progestogen. There seems to be no reason why, in contemporary gynaecological practice, the pill might not be used in the management of women with small fibroids where contraception is needed or where there is associated menorrhagia. Uterine size can easily be monitored by ultrasound.
Androgens Androgenic steroids may be used to suppress menstruation but there is little experience of their use in menorrhagia associated with fibroids. Danazol is effective in the management of dysfunctional uterine bleeding (Chimbira et al, 1979) but there have been no published reports of significant reduction in the volume of uterine fibroids. Another less well known androgen is gestrinone, a trienic 19-norsteroid. In a large series of 97 women with fibroids (Coutinho et at, 1986), reduction of mean uterine volume by 20% was reported after 4 months of therapy when 7.5-10 mg was given orally each week in divided doses. Vaginal administration was ineffective in reducing uterine volume. Menorrhagia was relieved, with 96% of the women becoming amenorrhoeic after 4 months of treatment. Gestrinone may be of value in the medical management of fibroids although side-effects related to its androgenicity have not been fully evaluated.
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LHRH analogues in the management of uterine fibroids
Analogues of L H R H are derived from the parent compound by substitutions in the decapeptide chain which give increased potency and duration of action. Both agonists and antagonists are available but clinical experience with the agonists is considerably more advanced (see Fraser and Baird, 1987). The rationale for the use of these compounds in the treatment of fibroids is the ovarian suppression which results from their administration. A single dose of an L H R H agonist stimulates gonadotrophin secretion and release (Sandow, 1983), while prolonged administration causes downLU Z
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regulation of the pituitary with consequent failure of ovarian follicular development and anovulation (Figure 4). L H R H agonists can be administered by nasal spray, subcutaneous injection or slow-release depot. Two preparations are licensed for use in the UK, namely buserelin nasal spray (Suprefact, Hoechst) and goserelin subcutaneous depot (Zoladex, ICI). The latter is administered from a pre-packed syringe in the form of a biodegradable rod from which the agonist is released at a constant rate over 28 days. Depot administration is more convenient and gives more reproducible piuitary-ovarian suppression than the intranasal route (West and Baird, 1987). There are now a number of published studies which have demonstrated shrinkage of uterine fibroids and relief of menstrual problems during shortterm therapy with various L H R H agonists (see review by West, 1989). Complete amenorrhoea is usual after the initial treatment cycle and a significant rise in haemoglobin concentration, haematocrit and serum iron concentration during therapy has been demonstrated (Friedman et al, 1988). Treatment has been by daily subcutaneous injection (Maheux et al, 1985; Coddington et al, 1986), subcutaneous (West et al, t987) or intramuscular (Van Leusden, 1986) depot or by intranasal spray (Maheux et al, 1987). Ovarian suppression and fibroid shrinkage are greater with the subcutaneous than the intranasal route (Friedman et al, 1987) because of poor absorption of the latter, although successful results have been reported with buserelin nasal spray given at a dose of 400 Ixg three times daily (Maheux et al, 1987). Maheux initiated treatment with subcutaneous injections for the first 2 weeks of treatment to achieve more rapid pituitary desensitization. Unfortunately, regardless of the route of administration, shrinkage of the fibroids is rarely complete and is not sustained after cessation of therapy. Reduction of uterine volume by approximately 55% after 6 months therapy has been reported by several different groups (see West, 1989). The greatest reduction in volume appears to occur in the first three months and the fall flattens off thereafter (Figure 5). As yet it is not known whether prolonged 600-
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Figure 5. Reductionof uterine volume(mean +_SD) measuredby ultrasound during 6 months therapy with goserelin depot 3.6 mg every 28 days. Resultsfrom 12 womenshowingmaximal reduction during the initial 3 months, with little change thereafter. The post-treatment measurement was taken 3 months after administration of depot 6.
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C. P. WEST AND M. A. LUMSDEN
therapy would lead to permanent fibroid regression. If such agents are to be an alternative to surgery, therapy is therefore potentially long term. This carries possible consequences of a prolonged hypoestrogenic state, particularly vasomotor side-effects, atrophic vaginitis and bone mineral loss. Many women will be happy to tolerate the side-effects, when compared to their menstrual symptoms but bone loss (Matta et al, 1988) is potentially more serious and is the single factor preventing the widespread use of L H R H agonists in women with fibroids. Nevertheless, these agents offer an alternative to surgery for women who have medical contraindications to surgery for example cardiovascular disease or obesity. They may also be useful for symptomatic women approaching the age of the natural menopause where ovarian suppression is less of a problem and surgery may be difficult to justify on cost-benefit terms.
Future role of LHRH agonists in the management of fibroids There are ways in which the adverse effects of L H R H agonists may be overcome in the future. Many women treated with L H R H agonists show incomplete ovarian suppression, even with depot administration (Figure 6). If, as in the example shown, fibroid volume remains stable, partial ovarian suppression with L H R H agonists administered intranasally or by low-dose depot may be suitable for maintenance therapy provided that symptoms are controlled. In practice this may lead to irregular bleeding and a risk of unopposed oestrogen stimulation of the endometrium (Schmidt-Gollwitzer et al, 1981) so that low-dose cyclical gestogens would be needed to maintain 160-
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FIBROIDS AND MENORRHAGIA
369
regular endometrial shedding. Such therapy has yet to be evaluated in the treatment of fibroids and associated menorrhagia. An alternative strategy would be to abolish ovarian activity with an agonist of L H R H and then to add another agent with the object of enhancing shrinkage of the fibroids while preserving bone mineralization and minimizing vasomotor and other side-effects. Progestogens should fulfill these criteria but our results and those of Friedman et al (1988) have indicated that addition of medroxyprogesterone acetate (MPA) 15-20 mg daily from the start of therapy prevents the initial rapid fibroid shrinkage seen with the L H R H agonist alone. The mechanism of this effect is not clear. These results do not exclude the possibility that addition of MPA at a later stage of therapy may be of value in maintenance of response as MPA does reduce the frequency of hot flushes while maintaining menstrual suppression. Addition of the anti-oestrogen tamoxifen should theoretically enhance fibroid shrinkage by blocking the effects of residual circulating oestrogen. However when given in combination from the start of therapy, tamoxifen also prevents fibroid shrinkage even though pituitary--ovarian suppression is enhanced (Lumsden et al, 1989b). These results suggest that tamoxifen paradoxically has oestrogen agonist actions in women rendered hypooestrogenic with L H R H agonists. If the object of therapy is symptomatic control rather than complete fibroid regression, an alternative approach is the use of low-dose hormone replacement therapy in combination with an L H R H agonist depot. Preliminary experience in 10 premenopausal women treated with goserelin with the addition of cyclical sequential low dose Premarin (0.3 mg) and Provera after three months (Maheux et al, 1988) has shown that fibroid volume appears to remain stable with good control of symptoms. Although promising, this and other similar approaches to the management of fibroids require further evaluation in larger numbers of women before they can be regarded as a true alternative to surgery. L H R H agonists as a preoperative adjunct to surgery
There are a number of ways in which agonists of L H R H may be a valuable adjunct to surgery in women with large and symptomatic uterine fibroids. Arrest of menorrhagia and correction of anaemia will improve the clinical state of the patient and may avoid transfusion. Reduction of the size of the uterus may improve surgical access and enable the use of a more cosmetic surgical incision. It may, in some cases, enable vaginal rather than abdominal hysterectomy to be performed. During therapy with an L H R H agonist, a reduction of bloodflow through the uterine arteries and through the major arteries supplying individual fibroids has been demonstrated using Doppler ultrasound (Matta et al, 1988) and this reduced vascularity may be associated with a reduction in operative blood loss. In a pilot study of 13 women pre-treated for 3 months with goserelin, compared with 14 untreated controls, blood loss at hysterectomy was significantly lower in the treated women (Lumsden et al, 1987). In addition, postoperative pyrexia was less frequent in the treated group. We are currently conducting a larger,
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placebo-controlled, randomized, multicentre study to assess the value of L H R H agonist therapy prior to hysterectomy. There is also the possibility that preoperative treatment with L H R H agonists will be useful in women undergoing conventional myomectomy or hysteroscopic resection of submucous fibroids. Myomectomy is frequently complicated by haemorrhage and there is a high rate of postoperative adhesions (Bonney, 1931; Rubin IC, 1942), presumably related to oozing from surgical incisions and this has an adverse effect on later fertility. Current experience of the use of L H R H agonists prior to myomectomy is limited. In a small personal series, Shaw (1989) reported a significant reduction in operative blood loss but more difficulty in enucleation of the fibroids following pretreatment with L H R H agonist. Clearly there is a need for multicentre evaluation of this approach, particularly in relation to longterm results. SUMMARY
Fibroids are an important cause of menorrhagia, resistant to conventional methods of medical treatment. The mechanism of their effect on menstrual blood loss is poorly understood but may involve abnormalities of local venous drainage, enlargement of the uterine cavity and abnormalities in prostaglandin production. Their cause remains unknown although it has long been assumed that they are oestrogen-dependent. In the past, study of their aetiology, prevention and treatment has received scant attention. Recent developments including measurement of tissue receptors for steroids and growth factors, non-invasive methods of monitoring fibroid growth and the use of L H R H agonists have enabled further study of their nature and of their response to therapy although much work remains to be done. The majority of women with uterine fibroids associated with menorrhagia are treated by hysterectomy although developments in endoscopic surgery have enabled a more conservative approach in some circumstances. L H R H agonists are the only medical agents which cause substantial shrinkage of fibroids although regression is not permanent. These agents are of value in short-term relief of symptoms and are likely to be a useful adjunct to surgery by reducing both uterine volume and bloodflow. However, because of the consequences of prolonged ovarian suppression, they are not suitable for long-term use unless there are medical contraindications to surgery. It remains to be seen whether their use in low-dose regimens or in combination with other agents will provide a successful, safe and cost-effective alternative to hysterectomy in women whose primary problem is heavy menstrual loss. They do however offer a means of conserving reproductive function in women wishing to retain this option. REFERENCES Aharoni A, Reiter A, Golan D, Paltiely Y & Sharf M (1988) Patterns of growth of uterine leiomymomas during pregnancy. A prospective longitudinal study. British Journal of Obstetrics and Gynaecology 95: 510-514.
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Bonney V (1931) The technique and results of myomectomy. Lancet i: 171-177. Buttram VC & Reiter RC (1981) Uterine leiomyomata: etiology, symptomatology and management. Fertility and Sterility 36: 433-445. Chegini N, Rao CV, Wakim N & Sanfilippo J (1986) Binding of 125I-epidermal growth factor in human uterus. Cell and Tissue Research 246: 543-548. Chimbira TH, Cope E, Anderson ABM & Bolton FG (1979) The effect of danazol on menorrhagia, coagulation mechanisms, haematological indices and body weight. British Journal of Obstetrics and Gynaecology 86: 46-50. Cochrane WJ & Thomas MA (1974) Ultrasound diagnosis of gynecologic pelvic masses. Radiology 110: 649-654. Coddington CC, Collins RL, Shawker TH et al (1986) Long-acting gonadotrophin hormonereleasing hormone analog used to treat uteri. Fertility and Sterility 45: 624-629. Corscaden JA & Singh BP (1958) Leiomyosarcoma of the uterus. American Journal of Obstetrics and Gynecology 75: 149-153. Coutinho EM, Boulanger GA & Goncalves MT (1986) Regression of uterine leiomyomas after treatment with gestrinone, an antiestrogen, antiprogesterone. American Journal of Obstetrics and Gynecology 155: 761-767. Davis J (1987) The principles and use of the neodymium-YAG laser in gynaecological surgery. Balliere's Clinical Obstetrics and Gynaecology 1: 331-352. Deligdish L & Loewenthal M (1970) Endometrial changes associated with myomata of the uterus. Journal of Clinical Pathology 23: 676-680. Dickson RB, H u f K-K, Spencer EM & Lippman ME (1986) Induction of epidermal growth factor-related polypeptides by 17J3-estradiol in MCF-7 human breast cancer cells. Endocrinology 118: 138-142. Farber M, Conrad S, Heinrichs W & Herrmann W (1972) Estradiol binding by fibroid tumours and normal myometrium. Obstetrics and Gynecology 40: 479-486. Farrer-Brown G, Beilby JOW & Tarbit MH (1971) Venous changes in the endometrium of myomatous uteri. Obstetrics and Gynecology 38: 743-751. Filicori M, Hall DA, Loughtin JS et al (1983) A conservative approach to the management of uterine leiomyomata: pituitary desensitisation by a luteinizing hormone-releasing hormone analogue. American Journal of Obstetrics and Gynecology 147: 726-727. Fraser HM & Baird DT (1987) Clinical applications of LHRH analogues. Balliere's Clinical Endocrinology and Metabolism 1: 43-70. Friedman AJ, Barbieri RL, Benacerraf BR & Schiff I (1987) Treatment of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin-releasing hormone agonist. Fertility and Sterility 48: 560-564. Friedman A J, Barbieri RL, Doubilet PM, Fine C & Schiff I (1988) A randomised double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertility and Sterility 49: 404--409. Goldrath MH, Fuller TA & Segal S (1981) Laser photovaporisation of the endometrium for the treatment of menorrhagia. American Journal of Obstetrics and Gynecology 140: 14-19. Goldzieher JW, Maqueo M, Ricard L, Aguilar JA & Canales E (1966) Induction of degenerative changes in uterine myomas by high dose progestin therapy. American Journal of Obstetrics and Gynecology 96: 1078-1087. Gonzalez F, Lakshmanan J, Hoath S & Fisher DA (1984) Effect of estradiol-1713 on uterine epidermal growth factor concentration in immature mice. Acta Endocrinologica 105: 425-428. Goodman AL (1946) Progesterone therapy in uterine fibromyomata. Journal of Clinical Endocrinology and Metabolism 6: 402-408. Hallez JP, Netter A & Cartier R (1987) Methodical intrauterine resection. American Journalof Obstetrics and Gynecology 156: 1080-1084. Hannigan EV & Gomez LG (1979) Uterine leiomyosareoma: a review of prognostic clinical and pathological features. American Journal of Obstetrics and Gynecology 134: 557-564. Healy DL, Lawson SR, Abbott M, Baird DT & Fraser HM (1986) Towards removing uterine flbroids without surgery: subcutaneous infusion of a luteinizing hormone-releasing hormone agonist commencing in the luteal phase. Journal of Clinical Endocrinology and Metabolism 63: 619-625. Hofman GE, Rao CHV, Barrows GH, Rossano LT & Sanfilippo JS (1984a) Prostaglandin E
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Pickles VR, Hall WJ, Best FA & Smith GN (1965) Prostaglandins in endometrium and menstrual fluid from normal and dysmenorrhoeic subjects. British Journal of Obstetrics and Gynaecology 72: 185-192. Pollow K, Geilfuss J, Boquoi E & Pollow B (1978) Estrogen and progesterone binding protein in normal human myometrium and leiomyoma tissue. Journal of Clinical Chemistry and Clinical Biochemistry 16: 503. Puuka MJ, Kontula KK, Kauppila AJ, Janne OA & Vihko RK (1976) Estrogen receptor in human myoma tissue. Molecular and Cellular Endocrinology 6: 35--44. Randall JH & Odell LD (1943) Fibroids in pregnancy. American Journal of Obstetrics and Gynecology 46: 349--357. Rees MCP & Turnbull A (1985) Leiomymomas release prostaglandins. Prostaglandins, Leukotrines and Medicine 18: 65-68. Richards DH (1973) Depression after hysterectomy. Lancet ii: 430-433. Ross RK, Pike MC, Vessey MP et al (1986) Risk factors for uterine flbroids: reduced risk associated with oral contraceptives. British Medical Journal 293: 359-362. Rubin A & Ford JA (1974) Uterine fibromyomata in urban blacks. South African Medical Journal 48: 2060. Rubin IC (1942) Progress in myomectomy: surgical measures and diagnostic aids favoring lower morbidity and mortality. American Journal of Obstetrics and Gynecology 44: 196-212. Rybo G, Leman J & Tibblin R (1985) Epidemiology of menstrual blood loss. In Baird DT & Michie EA (eds) Mechanisms of menstrual bleeding, pp 181-193. New York: Raven Press. Sandow J (1983) Clinical applications of LHRH and its analogues. ClinicalEndocrinology 18: 571-592. Sampson JA (1913) The influence of myomata on the blood supply'of the uterus with special reference to abnormal uterine bleeding. Surgery Gynecology and Obstetrics 16: 144-180. Schmidt-Gollwitzer M, Hardt W, Schmidt-Gotlwitzer K, vonder Ohe M & Nevinny-Stickel J (1981) Influence of the LH-RH analogue buserelin on cyclic ovarian function and on endometrium. A new approach to fertility control? Contraception 23: 187-195. Sciarra JJ & Valle RF (1977) Hysteroseopy: A clinical experience with 320 patients. American Journal of Obstetrics and Gynecology 127: 340-348. Scottish Hospital In-Patient Statistics (1985) Information Services Division, Scottish Health Service Common Services Agency. Segaloff A, Weed JC, Sternberg WH & Parson W (1949) The progesterone therapy of human uterine leiomyomas. Journal of Clinical Endocrinology and Metabolism 9: 1273-1291. Shaw RW (1989) Data presented at International Symposium on Endocrine Therapy, Monaco, November 1988, proceedings to be published. Sheets EE, Tsibris JCM, Cook NI et al (1985) In vitro binding of insulin and epidermal growth factor to human endometrium and endocervix. American Journal of Obstetrics and Gynecology 153: 60-65. Smith CJ (1952) Hysterectomy for benign pelvic conditions. American Journal of Obstetrics and Gynecology 64: 1211-1220. Smith SK, Abel MH, Kelly RW & Baird DT (1981a) Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. British Journal of Obstetrics and Gynaecotogy 88: 434-442. Smith SK, Kelly RW, Abet MH & Baird DT (1981b) A role for prostaeyclin in excessive menstrual bleeding. Lancet i: 522-524. Spellacy WN, LeMaire WJ, Buhl WC, Birk SA & Bradley BA (1972) Plasma growth hormone and estradiol levels in women with uterine myomas. Obstetrics and Gynecology 40: 829-834. Staros JV, Cohen S & Russo RW (i985) Epidermal growth factor receptor: characterisation of its protein kinase activity. In Cohen P and Houslay M (eds) Molecular Mechanisms of Transmembrane Signalling, pp 253--277. Elsevier Science Publishers. Thornton WN & Carter JP (1951) Sarcoma of the uterus, a clinical study. American Journal of Obstetrics and Gynecology 62: 294-301. van Leusden H (1986) Rapid reduction of uterine myomas after short-term treatment with microencapsulated D-Trp6-LHRH. Lancet ii: 1213. West CP (1989) LHRH analogues in the management of uterine fibroids, premenstrual
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syndrome and breast malignancies. Balliere's Clinical Obstetrics and Gynaecology 2: 689-709. West CP & Baird DT (1987) Suppression of ovarian activity by Zoladex depot (ICI 118630), a long-acting luteinizing hormone releasing hormone agonist analogue. Clinical Endocrinology 26: 213-220. West CP, Lumsden MA, Lawson S, WiUiamson J & Baird DT (1987) Shrinkage of uterine fibroids during therapy with goserelin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot. Fertility and Sterility 48: 45-51. Wilson EA, Yang F & Rees ED (1980) Estradiol and progesterone binding in uterine leiomyomata and in normal uterine tissues. Obstetrics and Gynecology 55: 20-24. Witherspoon JT (1935) The hormonal origin of uterine fibroids: a hypothesis. American Journal of Cancer 24: 402-406. Witherspoon JT & Butler VW (1934) The etiology of uterine fibroids with specific reference to the frequency of their occurrence in the negro: a hypothesis. Surgery Obstetrics and Gynecology 58: 57-61. Ylikorkala O & Pekonen F (1986) Naproxen reduces idiopathic but not fibromyomata-induced menorrhagia. Obstetrics and Gynecology 68: 10-12.