19.1.1 Uterine Fibroids

Uterine fibroids (UFs), also known as leiomyomas or myomas, are the most common benign gynaecologic neoplasm in premenopausal women worldwide and estimated to occur in 7–8 women out of 10 during their lifetime [1]. The aetiology behind UFs is thought to involve genetic, biologic, and environmental factors [1]. Growth factors have been implicated in certain molecular processes involved in the pathogenesis of UFs which includes inflammation, cell proliferation, fibrosis, and angiogenesis [2]. Numerous studies and clinical observations have shown that growth of UFs is dependent on ovarian steroid hormones. Accordingly, there have been no documented cases of UFs prior to menarche, while its prevalence increases with age and peaks during the fifth decade of life [3]. Consequently, the risk tends to decline after menopause, especially in women over the age of 70 years [4]. About 20% of UF patients present with heavy or abnormal bleeding and pelvic pressure; additionally, UFs can cause infertility or loss of pregnancy [2].

19.1.2 Ovarian Steroid Hormones and Uterine Fibroids

The role of oestrogen and progesterone has been critical in understanding the pathogenesis of UFs and how to manage them accordingly. Fibroids have an increased expression of oestrogen receptors (ERs) and progesterone receptors (PRs) as compared to the adjacent myometrium [5]; moreover, oestrogen recently has been shown to increase the expression of PRs, thus increasing the sensitivity of progesterone-responsive tissue including UFs to its actions [6].

Evidently, fibroid growth has been suppressed when treated with a continuous gonadotrophin-releasing hormone (GnRH) agonist for a period of 3 months, this is due to inhibition of oestrogen and progesterone release in response to GnRH receptor down-regulation at the pituitary gland, thus mimicking a postmenopausal hormonal profile [7]. Combined, these findings implicate the critical role of ovarian steroid hormones, especially progesterone, on fibroid growth [8]. Other clinical observations have noted success in suppressing fibroid growth with therapies targeting oestrogen, progesterone, and their respective receptors [5, 6].

19.2.1 Menopause

Menopause, the permanent cessation of menstruation, happens due to a decline in ovarian function, while perimenopause is the period prior to complete cessation of menses, and it is marked by fluctuations in ovarian steroid hormones reflecting the woman’s transitions from her reproductive years to non-reproductive years. Postmenopause is described as the period following a 12-month history of amenorrhea, signifying unresponsive ovaries and a collapse of the hypothalamic–pituitary–ovarian axis [9, 10]. In the United States, the average age for menopause is between 50 and 52 years. Women will typically present with hot flashes, night sweats, insomnia, vaginal atrophy, dysuria, urinary urgency, and sexual dysfunction [11].

19.2.2 Uterine Fibroids in Postmenopausal Women

Postmenopausal women classically have been found to have smaller, shrinking, and fewer fibroids, most likely due to the decline in ovarian steroid hormones [12]. Early onset of menarche and late onset of menopause act as risk factors for increased incidence of UFs. Noticeably, by the time women reach the age of 50, it is estimated that over 80% of black women and nearly 70% of white of women will have developed at least one fibroid during their lifetime [1]. Thus, reaching menopause does not totally eliminate the risk of new fibroids being diagnosed and women in the perimenopausal period should be considered to have higher risk of developing UFs. It is also possible that existing fibroids may continue to grow at a higher rate with an increase in patients’ age [13].

A large cohort study of teachers from California found that among 1,790 subjects, over 30% of those with newly diagnosed fibroids were between the ages of 45 and 49 years, followed by the second highest incidence in the age group of 50–54 years. The study results also showed that highest prevalence overall was between 45 and 49 years, with 40–44 years as a close second. The study trends also indicated a decline in newly diagnosed fibroids from 50 years old onwards, but it remained above 1% until the age of 80 years [14].

19.2.3 Postmenopausal Fibroids and BMI

The California teachers cohort study reported a statistically positive correlation between high body mass index (BMI) among premenopausal and perimenopausal women and surgical diagnosis of UFs. Such association desisted once women became postmenopausal [14]. Furthermore, a large prospective cohort study exploring the impact of obesity and hormone replacement therapy (HRT) on fibroids in postmenopausal women documented that obesity (defined by the World Health Organization as BMI >30 kg/m²) doubled the risk of UFs independent of HRT use [15]. The investigators went on to state that the use of HRT increased the risk of fibroids, regardless of BMI.

As uterine fibroids are known to be oestrogen-responsive, the increase in adiposity seen in obese women is likely to create a higher oestrogenic environment from the peripheral conversion favouring oestrogens. The study results signified that postmenopausal women continue to deal with fibroids, and the highest risk of surgically confirmed fibroids was found in obese women who had used HRT [15].

19.2.4 Postmenopausal Fibroids and Aromatase Enzyme Expression

Fibroid cells were shown to express the enzyme aromatase; therefore, they are able to locally synthesize oestrogen from androgenic substances such as androstenedione. This may explain why fibroids sometimes do not consistently regress in postmenopausal women, and this suggests a possible therapeutic role for aromatase inhibitors in the treatment of symptomatic fibroids in premenopausal and menopausal women. Moreover, aromatase is present in subcutaneous fat, so aromatase activity and plasma oestrogen levels correlate with BMI in postmenopausal women. This again supports the possible therapeutic benefit of an aromatase inhibitor in obese postmenopausal women [16–19].

19.2.5 Postmenopausal Fibroids and Bone Health

Postmenopausal loss of oestrogen greatly increases the risk of bone loss and, subsequently, development of osteoporosis [11]. Conversely, hyperoestrogenic states, such as obesity, have been shown to have protective effects on bone mineral density (BMD) even after factoring in mechanical load on bones [20]. Women with UFs are thought to have higher intrinsic oestrogen levels throughout their lifetime, which raises the question of whether the presence of fibroids influences bone health. As such, a prospective study published in 2006 demonstrated lower fracture risk and better bone health in peri- and early postmenopausal women who underwent hysterectomies for symptomatic UFs and never used HRT [20]. The study found a 31% reduction in any type of fracture in postmenopausal women with UFs in comparison to women without fibroids. The assumption is that fibroids causing symptoms severe enough to require hysterectomy are typically large and may have a higher intrinsic oestrogen level than smaller fibroids not requiring hysterectomies [20].

19.2.6 Leiomyosarcoma

Continued growth of any uterine masses and/or bleeding after menopause is worrisome and urgently warrants further evaluation for possible uterine sarcoma. Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma; they are rare but highly aggressive tumours with a poor long-term survival rate and account for an estimated 1% of all uterine malignancies [21]. Most investigators believe that leiomyosarcomas arise de novo from the myometrium and are not a progression from UFs [22]. They typically present with abnormal vaginal bleeding, pelvic pain, and pelvic mass, which all paint a similar clinical picture to UFs, thus making a preoperative diagnosis very difficult [22]. Occasionally, uLMS will have suspicious characteristics on MRI; also elevated serum levels of lactate dehydrogenase (LDH) isozyme 3 have been proposed as a possible biomarker [23]. However, these methods have poor positive predictive value and better uLMS diagnostics are urgently needed. Histologically, uLMSs are usually less well-circumscribed in comparison to fibroids and typically present as a single large myometrial mass [24].

All uLMS should be treated by en-bloc hysterectomy to avoid intraoperative abdominal spread of malignant cells [25]. However, as preoperative discrimination between benign UFs and malignant uLMS is currently difficult, laparoscopic power morcellation of possible uLMS lesions recently became a major surgical controversy [24, 26]. Morcellation uses a rotating blade to slice tissue into smaller pieces for ease of removal when undergoing a laparoscopic procedure [26]. Yet, it is argued that morcellation may lead to cancerous cells being spread throughout the abdominal cavity, thereby increasing the risk of further malignancy and possible worsening of patient prognosis. This is especially worrisome as one study estimates more than half of uLMS are not diagnosed until after surgical removal [26]. On the other hand, the FDA ban on power morcellation in the USA has led to a surge in open gynaecologic surgeries, with the expected increase in morbidity and complications [27].

19.2.7 Rare Cases of Postmenopausal Fibroids

Many case reports of rare, different types of fibroids in postmenopausal women have been published; for example, a severely calcified fibroid of broad ligament was identified in a 49-year-old postmenopausal woman and treated with hysterectomy [28], and another case of a large uterine fibroid with associated secondary polycythaemia was presented in a postmenopausal woman who underwent total abdominal hysterectomy [29]. A rare case of ovarian leiomyoma coexisting with a uterine lipoleiomyoma in a 59-year-old postmenopausal woman can postulate a common pathway as a stimulus for further research [30]. Other cases include a 23 kg giant fibroid removed from a 67-year-old postmenopausal woman that mandated urgent surgery [31], an ovarian leiomyoma [32], and a paraurethral leiomyoma [33].

19.3.1 Hormone Replacement Therapy

Many postmenopausal women opt to use hormone replacement therapy (HRT) due to its effectiveness to ameliorate symptoms associated with menopause as well as slow the progression of osteoporosis [11]. Hormone therapy can also provide cardioprotective effects during the first 10 years of early menopause [34]. As the natural regression of fibroids during menopause is understood to be due to the withdrawal of oestrogen and progesterone, supplementation of ovarian hormones in postmenopausal women has understandably made many clinicians apprehensive, due to the fear that therapy will increase fibroid size or at the very least prevent their regression. The use of HRT, however, can raise concern in women with a history of fibroids, as these hormones play a pivotal role in UF growth [35, 36].

Although HRT in postmenopausal women with fibroids may cause fibroid regrowth, it is not significant enough to contraindicate use, as most women will remain asymptomatic. Research on effects of HRT on fibroids remains inadequate, with conflicting and inconsistent results among many studies [37]. Nevertheless, it is suggested that women opting to use HRT should have ultrasound follow-ups every 3 months, and that therapy should be discontinued if fibroids show an increase in size after starting HRT [37].

19.3.2 Clinical Studies of HRT Effect on Postmenopausal Fibroids

In one trial, postmenopausal women were treated with continuous combined regimens of conjugated equine oestrogen (CEE) 0.625 mg/day along with oral medroxyprogesterone acetate (MPA) at 5 mg/day [38]. This trial showed increased growth of UFs during the first 2 years of therapy in comparison to women not on HRT. However, during the third year of therapy, there was a significant reduction of fibroid volumes, dropping from 13.5% of women experiencing fibroid growth in the first 2 years to 8.1% after the third year [38]. Several prospective studies have affirmed that fibroid growth peaks within the first 2 years of combined hormone therapy [14]. Another study compared 50 μg transdermal oestradiol plus 5 mg oral MPA continuously versus a regimen of 0.625 mg oral CEE plus 2.5 mg oral MPA continuously [36]. The results of this trial showed significant increase in fibroid size in the transdermal oestradiol group with 5 mg MPA after 1 year of therapy and no change in the oral CEE plus 2.5 mg MPA group; it also noted that fibroid size immediately shrunk after discontinuing therapy. These results suggest transdermal oestrogens and the increased dose of MPA may put patients at more risk for increase in fibroid size.

However, clinically, most studies have shown women remain asymptomatic and have low study dropout rates, regardless of whether the women had fibroid growth. Due to the increased risk of endometrial malignancy from unopposed oestrogen therapy, combined regimens are preferred [39]. Consequently, if therapy does include progestin, it is advised to use the lowest efficacious dose to avoid increased risk of fibroid growth [40].

19.3.3 Tibolone

Tibolone, a synthetic steroid with semi-oestrogenic, progestogenic, and androgenic activities, is used to treat menopausal symptoms. It seems to have the least effect on fibroid growth in postmenopausal women and so is preferred over combination therapies. One small study conducted with 56 postmenopausal women evaluated tibolone (2.5 mg) compared to transdermal HRT of oestradiol 0.05 mg for 4 weeks and norethisteron acetate 0.25 mg for 2 weeks [41]. The results showed that neither tibolone nor combined transdermal therapy had statistical significance for fibroid growth. Conversely, another small randomized study showed statistically significant increase in uterine volume, fibroid size and numbers with oestrogen–progestin therapy (transdermal system releasing 0.05 mg/day oestradiol with oral 10 mg/day MPA for 12 days), especially after 6 and 12 months of therapy [42]. One randomized trial indicated postmenopausal women who received tibolone 2.5 mg showed no statistical significance in fibroid volume change after 1 year of treatment [36]. Overall, most studies showed preference for tibolone over combined or transdermal HRT, as it does not increase uterine and fibroid size while still providing relief from menopausal symptoms [36, 42].

19.4.1 Aromatase Inhibitors

Aromatase inhibitors markedly suppress plasma oestrogen levels in postmenopausal women by inhibiting or inactivating aromatase enzyme. The ability of aromatase inhibitors to suppress endogenous oestrogen levels in postmenopausal women has led to their use as adjuvant therapy in the treatment of breast cancer [16].

Anastrozole, a third-generation non-steroidal aromatase inhibitor, may prove of value in treating fibroid-related uterine bleeding in obese postmenopausal women. Moreover, women taking aromatase inhibitors seem less likely to experience hot flashes than those using tamoxifen.

Use of aromatase inhibitors, in contrast to tamoxifen use, does not increase the risk of endometrial neoplasia or thromboembolism. A study has reported the successful use of an aromatase inhibitor in reducing the dimensions of a fibroid tumour causing urinary retention in a perimenopausal woman [18, 19].

19.4.2 Selective Oestrogen Receptor Modulators (SERMs)

Selective oestrogen receptor modulators (SERMs) elicit tissue-specific actions through a mixed agonistic and antagonistic effect on oestrogen receptors [5]. Two SERMs have been investigated: tamoxifen, which is used in treating breast cancer especially after surgical resection, and raloxifene, which is used in the prevention of osteoporosis. In one study, 17 postmenopausal women with fibroids were given a regimen of tamoxifen 20 mg daily. At the time of follow-up, the study found a significant increase in overall mean fibroid volume and volume of each fibroid on ultrasound scan [36]. However, all women remained asymptomatic and none discontinued therapy. Additionally, Palomba and colleagues evaluated raloxifene in postmenopausal women with fibroids and concluded that it is safe for use after studying its effect on fibroid dimensions, growth, and symptom severity, especially that of abnormal uterine bleeding. Their results suggested raloxifene significantly decreased uterine fibroid size after 6, 9, and 12 cycles of therapy [7, 44]. Studies on the impact of therapy for fibroids should be performed not exclusively with premenopausal women but also with perimenopausal and postmenopausal women, both users and non-users of HRT.

19.4.3 Uterine Artery Embolization

A retrospective study was conducted to explore the efficacy of uterine artery embolization (UAE) for postmenopausal symptomatic fibroid treatment. In all, 88.9% of patients demonstrated resolution of symptoms. UAE therefore could be considered as an alternative treatment to hysterectomy [45].