Alessandro D. Genazzani1 , Elisa Chierchia1, Giulia Despini1 and Alessia Prati1
(1)
Department of Obstetrics and Gynecology, Center for Gynecological Endocrinology, University of Modena and Reggio Emilia, Modena, Italy
Alessandro D. Genazzani
Email: algen@unimo.it
17.1 Introduction
Uterine fibroids or myomas are the most frequent benign neoplasm during fertile life in women. It originates from the smooth muscle cells of the uterus (myometrium) [1], and it is frequently found at a gynecological examination or at ultrasound in almost 30 % of the women above 35 years of age. Myomas are usually asymptomatic, but in 30 % of the women, they can induce a variety of symptoms such as dysmenorrhea, menorrhagia, pelvic discomfort, infertility, recurrent abortion, and when there several myomas and/or when they are quite large and heavy, they can induce diseases for the compression of the tissues and/or organs close to the uterus, such as the bladder [2].
Fibroids usually develop in the uterus, but they can develop almost in any other organ such as the intestine, the skin, and the vascular system (intravenous leiomyomatosis) [2]. According to the place where a myoma develops, the symptoms are different and variable, thus affecting the choice of treatment [3]. In fact, fibroid location, size, and number influence signs and symptoms:
· Subserosal fibroids. Fibroids that project to the outside of the uterus (subserosal fibroids) can sometimes press on your bladder, causing you to experience urinary symptoms. If fibroids bulge from the back of your uterus, they occasionally can press either on your rectum, causing a pressure sensation, or on your spinal nerves, causing backache.
· Intramural fibroids. Some fibroids grow within the muscular uterine wall (intramural fibroids). If large enough, they can distort the shape of the uterus and cause prolonged, heavy periods, as well as pain and pressure [4].
· Submucosal fibroids. Fibroids that grow into the inner cavity of the uterus (submucosal fibroids) are more likely to cause prolonged, heavy menstrual bleeding and are sometimes a problem for women attempting pregnancy. They can be subdivided in types I and II according to the percentage (higher or lower than 50 %) of the fibroid located in the uterine cavity [5].
The common symptoms associated with uterine leiomyomas are irregular and/or excessive bleeding, which are the cause of anemia, pelvic pain, bowel and bladder dysfunction, and pain during sexual intercourse [2, 6]. On the basis of the severity of such symptoms, uterine fibroids are the most common indication for hysterectomy all over the world. Although some medical treatments have been proposed, up to now, none of them has been reported to be the perfect solution to avoid the need of surgery.
17.2 Pathogenesis of Uterine Leiomyoma/Fibroid
Up to now, it is not clear why women develop uterine fibroids; nevertheless, there are specific racial differences since the prevalence of fibroids is over threefold higher in black women compared with white women [7]. In addition, early menarche, heredity, nulliparity, obesity, PCOS, diabetes, and others have been reported to be major risk factors with the development of uterine fibroids [8].
According to recent studies, more than 50 % of the myomas have chromosomal abnormalities affecting various genes [6]. In addition to genetic factors, recently, epigenetic mechanisms such as DNA methylation and histone modification have been reported for myomas, thus supporting a high grade of gene deregulation compared to normal myometrium [6, 9].
It is well known that estrogen and progesterone and their specific receptors have specific effects on myoma growth and that their actions are in part mediated by growth factors [6, 8, 10] such as EGF, platelet-derived growth factors (PDGF), TGF, IGF, VEGF, activin, myostatin, IL6, and other cytokines. A specific key role is probably played by extracellular matrix (ECM) components such as fibronectin and proteoglycans [6, 11], but the presence of estradiol and progesterone remains crucial. Estradiol appears to be necessary to allow progesterone stimulatory action on fibroid growth, and both these gonadal steroids are necessary for the production of ECM components, such as collagen types I and II. In fact, collagen fibers are overexpressed during the follicular phase of the cycle, and the P receptor antagonist asopristil down-regulates collagen fiber synthesis in an in vitro model [11]. The action of estradiol in fibroid growth takes place through its receptor Erα. Estradiol from the general circulation, as well as locally produced, is involved. In fact, aromatase inhibitors are as effective as GnRH analogues in reducing fibroid volume with estradiol concentrations remaining normal to high in aromatase inhibitor users and low in GnRH analogue users [11]. Part of estradiol action on myomas growth is mediated through an IGF-1-stimulated production of the PCNA protein, which stimulates smooth muscle cells growth, and the BLC-2 protein, which inhibits apoptosis [12] (Fig. 17.1). As additional confirmation, cotreatment of GnRH analogue with progestins limited their therapeutic efficacy, while this was not observed in women cotreated with estrogens and progestins [13, 14]. Finally, it has been reported recently that the use of selective progesterone receptor modulators (SPRMs) induces fibroid shrinkage similarly to that of GnRH analogue, maintaining normal estradiol plasma levels, thus confirming the relevant role of P and P receptors (Pr) in fibroid growth [11].
Fig. 17.1
Estrogen and progesterone modulation of fibroid growth
17.3 Medical Treatment of Fibroids
The only treatment for fibroids that has been considered is myomectomy or hysterectomy or, in some cases, limited surgery such as myomectomy by hysteroscopy. Although surgery remains as the unique remedy when bleeding is out of any control, recently, new strategies have been developed to avoid hysterectomy, when possible.
Medical treatment of fibroid is intended to relieve heavy menstrual bleeding to limit anemia and all the related side effects. Unfortunately, at various levels, all these medical options induce anovulation and/or amenorrhea and, in several cases, have contraindications for pregnancy.
Actually, the medical options available are progestins, SERMs, aromatase inhibitors, GnRH analogues, and – the latest innovative remedy – SPRMs.
17.3.1 Progestins
For years, the use of oral or intramuscular progestins has been a classical treatment for abnormal dysfunctional bleeding (Table 17.1) since they act on the endometrium, but no great advantages have been reported on fibroids [6, 15]. This is probably due to the various characteristics of the progestins since some of them induce endometrial atrophy or suppress gonadotropin secretion. However, progestins, as well as P, induce fibroids growth, as above discussed, although some of them show some beneficial effects.
Table 17.1
Actual possible treatments for symptomatic uterine fibroids
|
Class |
Compound |
Effects on the patient |
Side effects |
|
Progestins |
NETA NOMAC Danazol LNG Dienogest LNG–IUD |
Bleeding control Bleeding control Bleeding control Bleeding control Bleeding control Bleeding control |
|
|
SERMs |
Raloxifene |
Limited efficacy |
Climateric symptoms |
|
Aromatase inhibitors |
Fibroid volume reduction |
Climateric symptoms |
|
|
GnRH analogues |
Leupreline acetate |
Bleeding control, fibroid volume reduction |
Climateric symptoms, osteopenia |
|
SPRMs |
Mifepristone Ulipristal acetate Asoprisnil Telapristone acetate |
Bleeding control Bleeding control, fibroid volume reduction Bleeding control Bleeding control, fibroid volume reduction |
PAECs PAECs PAECs PAECs |
One of the most used progestins is norethisterone acetate (NETA). NETA is a 19-nor-17α-ethynyltestosterone and has been demonstrated to modulate endometrium growth, reducing menstrual bleeding and, to some extent, has been demonstrated to reduce fibroids size with no side effects both when used alone during the luteal phase of the menstrual cycle [16] and when combined with estrogens as hormone replacement therapy.
Nomegestrol acetate (NOMAC), a 19-nor-progesterone derivative, has been demonstrated not to induce fibroid growth when coupled to estrogens both as contraceptive pill and as hormonal replacement therapy [17], but no relevant clinical data have been produced on fibroid treatment. Also danazol and levonorgestrel have been proposed to treat fibroids and with relatively good results [6, 18]. Recently, dienogest, a 19-nor-progesterone derivative, has been demonstrated to reduce leiomyomas growth and size in patients treated for endometriosis similarly to GnRH analogue [19]. Although dienogest has indications for the treatment of endometriosis, it is able to reduce abundant menstrual bleeding induced by fibroids (especially if intramural) since it acts specifically on the endometrium, inducing atresia.
Another interesting option is the intrauterine delivery of progestins by means of an intrauterine device (IUD). The only available system is the one with levonorgestrel, which has been approved by the FDA in the USA to treat abnormal and/or heavy menstrual bleeding [19]. In women with fibroids, it has been demonstrated to reduce menstrual bleeding and to improve anemia, thanks to the induction of atresia of the endometrium, but with minimal effects on the fibroids size [20].
17.3.2 Selective Estrogen Receptor Modulators (SERMs)
This family of drugs is nonsteroidal estrogen ligands and has been shown to have agonist or antagonist effects according to the target tissue. The most known SERM used for breast cancer is Tamoxifen, but for fibroids, Raloxifene has been demonstrated to have an antiestrogenic effect on myomas [21] although the clinical efficacy on fibroids is limited [11].
17.3.3 Aromatase Inhibitors
Aromatase inhibitors belong to a family of steroidal (exemestane) and nonsteroidal (anastrozole, letrozole) drugs that interact with the activity of aromatase. Aromatase is a cytochrome P450 enzyme that transforms androgens into estrogens. Only one trial has been done using letroxole versus GnRH-a, and letroxole reduces fibroids size up to 46 %, but no data were given on bleeding [22].
17.3.4 GnRH Analogue
This is a well-known family of drugs structurally similar to the endogenous GnRH produced by hypothalamus. Their mechanism of action is simple: after binding to the GnRH receptor, there is a stimulation of gonadotropin release (flare-up) and then there is desensitization, blocking any further gonadotropin release. It is obvious that such an action induces within 15 days the dramatic reduction of gonadal steroids plasma levels to the menopausal range. The success of GnRH analogue treatment is due to the induction of amenorrhea to the hypoestrogenic milieu, which block both bleeding and fibroid growth, inducing their shrinking. GnRH analogues have also specific effects on growth factors; decrease paracrine, mitogenic, and angiogenic factors; and induce apoptosis [23, 24]. Treatment with GnRH analogues has been evaluated either alone or with an add-back treatment to reduce the side effects due to the hypoestrogenic condition. Usually, add-back is performed using progestins, estro-progestins, tibolone, and raloxifene, but progestins tend to antagonize GnRH analogue effects on fibroids. Raloxifene further reduces fibroids size but improves the vasomotor symptoms. Tibolone and estro-progestins seem to be less effective in antagonizing GnRH analogue effect and reduce climacteric symptoms significantly.
Although greatly effective on fibroids, GnRH analogues cannot be used for more than 6 months and after suspension fibroid volume increases again [25] together with abnormal bleeding.
17.3.5 Selective Progesterone Receptors Modulators (SPRMs)
SPRMs are a new family of drugs that selectively bind to progesterone receptor, with agonist, antagonist, or mixed activity (Fig. 17.2). Since the beginning ,in vitro experiments showed that fibroid cells treated with SPRMs such as ulipristal acetate (UPA), telapristone acetate, and asoprisnil induced a decrease of cell proliferation and apoptosis, while no effects were observed on normal myometrial cells [26–31].
Fig. 17.2
Progesterone receptor ligands show specific activity ranging from pure antagonist to pure agonist (SPRMs: Selective Progesterone Receptor Modulator)
In addition, UPA has been demonstrated to reduce ECM production, which is considered as a relevant determinant for connective and collagen growth [27].
In these last couple of years, a number of clinical studies have investigated the efficacy of SPRMs to treat myomas, with all of them (i.e., mifepristone, UPA, asoprisnil, telapristone acetate) being effective in reducing fibroid size as well as uterus volume [11, 13, 14, 25, 32–35] up to 53 % of their size. In addition, all such SPRMs maintain the reduced fibroid size for longer time interval than do GnRH analogue, up to 6 months after treatment discontinuation [11, 25].
A very interesting aspect is the fact that SPRMs suppress bleeding more rapidly than do GnRH analogues. Indeed, in a randomized trial, bleeding control was achieved and stopped within 7 days after UPA administration [25] compared with 21 days for the GnRH analogue group, and a high percentage of amenorrhea occurred with no hypoestrogenism [25]. Estradiol plasma levels were maintained close to 40–60 pg/ml all along UPA administration, avoiding all climacteric symptoms and all negative side effects on all estradiol-sensitive organs such as bones, bladder, and brain [25].
At present, UPA has been approved as the SPRM for treatment of fibroid at the daily dosage of 5 mg for 3 months [14, 25].
Recently, the treatment interval has been prolonged with UPA at the dosage of 10 mg/day for 3 months for four times with interval of 2 months in between each UPA treatment interval [33]. Such prolongation determined the maintenance of the reduced size of the fibroids together with a high percentage of amenorrheic condition (up to 90 %), and at the end of the last round of treatment, fibroids reached up to −72 % of their starting size [36].
What is interesting to mention is that according to surgeons’ experience, myomectomy that might occur after UPA treatment results to be much easier than those done after GnRH analogue administration since the cleavages of the fibroids are easily found and the amount of bleeding during surgery is much reduced (personal observation).
A peculiar aspect that has been raised when SPRMs were administered was the endometrium concerns. In fact, long-term (3–6 months) SPRM administration (mifepristone and asoprisnil) has been reported to induce nonphysiological endometrial changes characterized by dilated weakly secretory endometrial glands with few mitotic figures and stromal effects ranging from compaction to nonuniform edema [35, 37]. A panel of expert pathologists concluded that no safety concerns arise from these changes, which have been termed “progesterone receptor modulator-associated endometrial changes” (PAECs) [11, 38]. Data from PEARL I, II, and III studies using UPA [14, 25, 33] demonstrated that PAECs were not a real problem, and that although only 10–12 % of the patients had an endometrial thickening >16 mm, the endometrial histology did not demonstrate atypia, either simple or complex. PAECs disappeared after treatment suspension [14, 25, 33]. Interestingly, such PAECs aspect at the endometrial level has been reported also in women not receiving SPRMs and in 10 % of the women before the SPRMs administration [33].
In conclusion, fibroids represent a real problem especially when they are symptomatic and induce meno-metrorrhagia, anemia, pelvic discomfort, and pain. There have been various medical treatments available to moderate the bleeding, pain, and anemia before surgery for myomectomy and/or hysterectomy. Up to now, the gold standard treatment for such situation has been GnRH analogue administration, but this is a treatment that cannot be administered for a long interval of time. The availability of SPRMs, such UPA, now makes possible to treat and probably to avoid surgery in a high percentage of women with symptomatic fibroids, with no climacteric symptoms (i.e., hot flashes, insomnia, mood changes) and no negative effects on other organs such as bone and the urogenital tract. These new drugs can be useful to offer a chance to preserve an integer uterus in those women looking for potential fertility. SPRMs do not change the estrogenic milieu and permit also long-term treatment in women close to late 40s to delay/avoid surgery until menopause when fibroids show a natural regression.
According to all the data up to now reported, SPRMs, mainly UPA, are more effective on fibroid in acute as well as in chronic long-term treatment than the gold standard treatment, i.e., GnRH analogue.
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