Contemporary principles of therapeutic treatment of uterine fibroid
A.I. Evdokimov Moscow State University of Medicine and Dentistry
The selective modulators of progesteron receptors (SMPR) and the agonists оf GnRG (aGnRG) realize therapeutic effect at the central and local levels, they disrupt the functioning of the intracellular system of the realization of the biological effects of the factors of growth, sexual hormones and other substances, which facilitate the progression of myoma of womb.
The keywords: myoma of womb, endometriosis, hyperplasia of endometrium; hormones, the factors of growth, apoptosis, neoangiogenesis, extratcellulary matrix, Esmiya, Buserelin Depot.
Tikhomirov Alexander Leonidovich, Professor, Doctor of Medical Science, Professor of the Department of Obstetrics and Gynecology, Faculty of General Medicine of A.I. Evdokimov Moscow State University of Medicine and Dentistry. Address: 127473, Moscow, Delegatskaya ul., 20/1, Phone: (495) 178-28-31
Until recently, the possibilities for drug treatment of uterine fibroid were generally limited by an adjuvant approach with the short-term administration (due to possible undesirable effects) of agonists of gonadotropin-releasing hormone. Uterine fibroid actually remains a surgical pathology. However, for many women who want to avoid surgery, a significant need for effective medical treatment of this widespread disease remains. Uterine fibroid is diagnosed in 35-70% of women of reproductive age and recognized as a main reason for hysterectomies.
In the last 15 years the critical role of progesterone in stimulating the growth of fibroids was proved. In particular, we found that uterine fibroid usually develops during ovulatory menstrual cycle. This was proven by a number of analyses of functional tests of ovarian hormonal activity, investigation of sex hormones in blood and histological data in case of resection or removal of ovaries during uterine fibroid surgeries indicating the registration of yellow bodies and multiple corpus albicans in them. At the cellular level, progesterone causes the growth of leiomyoma cells, which is indicated by an increased expression of markers of proliferation in uterine fibroid during the luteal phase. Our previous immunohistochemical studies showed that up to 90% of cells proliferating uterine fibroid contain the active receptors of progesterone which is a stimulant of the epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-I) - (the main mitogens of myoma) and antiapoptotic proto-oncogene BCL 2, and so progesterone contributes to the growth of uterine fibroid . This arouses interest in studying the possibilities of the treatment of uterine fibroid using modulators of progesterone receptors.
It is known that the family of modulators of progesterone receptors includes pure agonists, such as progesterone itself or progestins, and, on the other hand, those of the biological spectrum - pure progesterone receptor antagonists. Selective modulators of progesterone receptors have mixed tissue-specific agonistic-antagonistic properties and take an intermediate position in the spectrum. The effects of progesterone as well as progesterone receptor antagonists and selective modulators of progesterone receptors are mediated in target tissues largely by progesterone receptors (PR) which belong to the family of ligand-activated nuclear receptors and are transcription factors.
The progesterone receptor exists as two distinct isoforms (A and B) expressed by the same gene with two different sites of the start of transcription but providing either of the isoforms. The structural configuration of PRA and PRB differs only in that PRB contains an N-terminal fragment of 164 amino acids which is absent in PRA. As a consequence, PRB contains three domains that activate transcription (AF-1, AF-2, and AF-3), while PRA contains only two domains (AF-1 and AF-2). The two isoforms of progesterone receptors have the same effect with respect to binding of steroid hormones and DNA, but have different functions depending on the cell type and the presence of an activator of expression of the target gene. In general, PRB is significantly more potent transcription activator than PRA. Under certain conditions, PRA is inactive as a transcription factor but can act as ligand-dependent transdominant repressor of other steroid receptors including PRB, estrogen receptors, androgen receptors, mineralocorticoid receptors and glucocorticoid receptors. PRA may act as this repressor in response to binding with agonists or progesterone antagonists. The isoforms of progesterone receptors may play different roles depending on tissue. The new selective progesterone receptor modulator Ulipristal acetate (Esmiya) affects progesterone receptors in myometrium, myomatous nodules, endometrium and inhibits ovulation without significant effect on the level of estrogen and anti-glucocorticoid activity. By 2013, selective anti-proliferative, pro-apoptotic and anti-fibrotic effect of Ulipristal acetate on myomatous nodules had been demonstrated in western countries in vitro. Also, the ability of Ulipristal acetate to reduce in the uterine fibroid expression of vascular endothelial growth factor, adrenomedullin and its receptors, to increase the degradation of extracellular matrix by an increase of matrix metalloproteinases and decrease of their tissue inhibitors and collagen was demonstrated in vitro. However, in vitro studies exclude an important role of pathogenetic autocrine-paracrine mechanisms which are integral units of complex signaling pathways, and the apoptosis index score without comparison with the level of mitotic activity and proliferation is not quite informative.
That is why, in the first stage of the study of Ulipristal acetate, the objective of our research was to conduct clinical and morphological study considering the major indicators of growth of uterine fibroid. In 2013 we selected a clinically homogeneous group of 13 patients with uterine fibroid by age (37-42 years), size of the uterus (corresponding to 16 weeks of pregnancy ) and dominant nodule (10 cm in diameter), its localization (interstitial with uterine cavity deformation), symptoms (menorrhagia). The three-month pre-operative treatment with Ulipristal acetate leads to a rapid cessation of heavy menstrual bleeding and reduction of the uterine fibroid volume without a risk of development of endometrial hyperplasia. The same clinical results were reported in randomized double-blind placebo-controlled studies abroad [2, 3]. In 2013 we conducted a study  and observed an induction of apoptosis and inhibition of proliferative and mitotic activity of uterine fibroid cells. However, reduction in the volume of uterine fibroid parenchyma only does not explain significant (by several times) reduction of the size as in simple uterine fibroids more than a third of their volume is represented by the stroma, the extracellular matrix. In addition, processes of angiogenesis play an important role in the growth of uterine fibroids. The interdepartmental (Moscow State University of Medicine and Dentistry named after A.I. Evdokimov) clinical and morphological study  conducted in 2014 showed that, as expected based on the results of works with the use of tissue cultures, Ulipristal acetate causes a decrease of uterine fibroid volume not only due to the induction of apoptosis, reduction of proliferative and mitotic activity, but also by inhibiting angiogenesis, production of growth factors (VEGF, EGF, FGF-2, TGF- 1) combined with an increased production of matrix metalloproteinases (MMP-2, -10, -12) and reduction of their tissue inhibitors (TIMP-1, -2, -3).This leads to a reduction of the vascular bed, remodeling and decrease of the volume of the extracellular matrix of fibroid. Simultaneous inhibiting influence on parenchymatous component, angiogenesis and extracellular matrix explains the mechanism of rapid, pronounced and prolonged reduction of the uterine fibroid volume under the influence of Ulipristal acetate.
Recent European studies of the mechanism of regressing effect of Ulipristal acetate on uterine fibroid explain even finer mechanisms. Certainly, uterine fibroid is hormone-dependent, and progesterone plays a critical role in its development and growth. However, the steroid-dependent growth of uterine fibroid is locally mediated by cytokines and growth factors [6,7]. In the myoma extracellular matrix which primarily ensures its growth, expression of activin A, the growth factor from the family of transforming connective tissue growth factor (TGF-beta) activating the synthesis of fibronectin (one of the most important components of the extracellular matrix) and vascular endothelial growth factor (VEGF-A) is increased.The ability of Ulipristal acetate to block activin A, its receptors and VEGF-A in the absence of such effects on the unchanged myometrium  is shown in vitro in the culture of smooth muscle cells of uterine fibroid. That is, activin A may be an additional studied and important target in the reduction of the uterine fibroid volume when administering Ulipristal acetate.
The clinical Study PEARL III conducted in 18 study centers in four European countries with the approval of the Guideline for Good Clinical Practice (GCP) of the International Conference on Harmonization included women of reproductive age, with at least one uterine fibroid 3 cm in diameter but not more than 10 cm, heavy menstrual bleeding and uterine size <16 weeks of pregnancy who had indications for surgery for uterine fibroids. 132 patients were selected in the study at the age of 18-48 years with a body mass index of 18 to 40 (kg/m2), regular menstrual cycles lasting 22-35 days and the level of follicle-stimulating hormone of ?20 IU/l, who received 4 intermittent three-month courses of the treatment with Ulipristal acetate at a dose of 10 mg a day.
The period out of the treatment between each course of Ulipristal acetate included one menstrual bleeding and the beginning of the second bleeding. Endpoints of the efficacy and safety were evaluated after the first course of the treatment, after each subsequent course of the treatment and 3 months after the last treatment. The results of the third phase of multicenter clinical studies demonstrated high efficacy and safety of repeated courses of the therapy of uterine fibroid with Ulipristal acetate. Thus, after the first three month course amenorrhea developed after four days on an average in 79% of women, and the volume of uterine fibroid decreased by 45% (from 25 to 66%). After 4 three-month courses the amenorrhea incidence reached 90%, and the uterine fibroid size reduced by 72% of the volume, which allowed some patients to avoid surgery due to significant and persistent regression of myomatous nodules. Under the influence of Ulipristal acetate, in the endometrium of the majority of women reversible (for several weeks and even after 4 courses of the therapy) benign changes called PAEC (PRM-Associated Endometrial Changes are changes in the endometrium associated with the use of modulators of progesterone receptors) develop. They underlie amenorrhea along with anovulation. After termination of the treatment menstruation usually returns in 4-5 weeks, and the reduction of uterine fibroid may remain for a period of up to 6 months. In addition, the treatment with Ulipristal acetate reduces the pain associated with uterine fibroid and improves the quality of life; there were no problems with regard to safety .
Benign uterine diseases, i.e. uterine fibroid, endometrial hyperplasia, adenomyosis (AM), represent an actual problem of modern gynecology, and their combination complicates the choice of organ-preserving treatment in women of different age groups. Considering the highest detection rate of uterine fibroids in conjunction with endometriosis in patients aged 40 to 50 years, it should be noted that in this period hyperplastic processes of endometrium (which in 70% of cases are presented in the form of a simple endometrial hyperplasia without atypia) may accompany these diseases due to the age-related anovulation. So, about 20-25% of women with combined hyperplastic uterine pathology in this age group are characterized by the presence of small myomas, adenomyosis and, in fact, by age-related hyperplastic processes in endometrium. How to treat them? Combined pathology – should we perform a hysterectomy? It is tempting, especially by laparoscopic access, it would seem that this is the most suitable group of patients for such a treatment.
However, after 2000 the question of excessive prevalence of hysterectomies in patients with benign uterine hyperplasia (about 650,000 a year in Russia, the USA and Europe) came up. At that, it is known that in Russia 90% of hysterectomies in women of the reproductive age is performed with absolutely benign uterine pathology.
The average age of patients undergoing the most common gynecological abdominal surgery, hysterectomy, in Russia is 40 years, and this inevitably leads to the development of post- hysterectomic syndrome characterized by severe (2-3 times) decrease in estrogen production already on day 2 even after hysterectomy even without appendages under conditions of tissue hypoxia after crossing the ovarian branch of the uterine artery. As a result, premature menopausal disorders develop, which not only reduce the quality of life of quite young women but also contribute to more rapid aging, or lead to a neсessity for the early use of the menopausal hormonal therapy with its all not fully resolved issues.
Therapeutic possibilities of GnRH agonists in relation to small stable uterine fibroids, adenomyosis, endometrial hyperplasia without atypia are tried out and well known. If modern hormonal contraception and ulipristal acetate may play a positive role in the stabilization of sizes of small myomas and adenomyosis; and progestins in the treatment of endometrial hyperplasia without atypia and endometriosis, what to do in case of a combination of these processes in one womb? Moreover, these hyperplastic processes in uterus may be associated with hormone-dependent benign breast diseases which, as it was found in recent years, can be both estrogen and progesterone-dependent. The administration of agonists of gonadotropin-releasing hormone (the most available of which is our domestic drug Buserelin-depo) is the most pathogenetically justified method for the purpose of steroid ablation. The active substance is included in microspheres, which provides constant concentration of the drug in blood within 28 days.
In addition to hormonal ablation against the background of desensitization of the pituitary gland and interruption of the hypothalamus -pituitary-ovaries-uterus axis , agonists of gonadotropin-releasing hormone reduce proliferation in uterine fibroid, endometriosis foci and eutopic endometrium due to the fact that Buserelin-depo directly binds to the cytoplasmic membrane of pathological cells by interacting with its specific receptors; inhibits products of genes associated with the G1 phase of the cell cycle, such as cyclin E and p33cdk2; inhibits proliferation by increasing the intracellular concentration of annexin V, endogenous protein kinase C inhibitor;
reduces the release of promitogenic cytokines IL-1? and VEGF? inhibition of proliferation and neoangiogenesis; induces apoptosis by increasing the activation of Fas / FasL - and Bax - mediated mechanism of apoptosis, reduces the effect of the antiapoptotic protein Bcl-2; depresses local production of estrogens; leads to a decrease in the expression of transforming growth factor and its receptors, which is accompanied by a decrease of the volume of myomatous nodules. In addition, against the background of the therapy with Buserelin-depo there is a significant reduction in the so-called extracellular signal-regulating kinases and focal adhesion kinases, which are integral units of intracellular signaling pathways activated by sexual hormones and growth factors [10-18].
In one of our studies diffuse endometrial hyperplasia (simple, complex hyperplasia without atypia) was diagnosed in 68 patients with small size myomas (up to 3 cm in diameter) and ultrasonographic evidence of adenomyosis at the age from 36 to 48 years old on the basis of histological studies of tissue after separate therapeutic and diagnostic curettage of the mucous membrane of the uterus (31 patients), hysteroscopy + curettage (28 patients), hysteroscopy + curettage + hysteroresectoscopy (9 patients).
For the treatment of concomitant gynecological pathology after receiving of histological results Buserelin depo was administered at a dose of 3.75 mg/m intramuscularly from the first days of the next menstrual period followed by the injection of the same dose every 28 days for 6 months under ultrasound investigations once every 3 months. For the final evaluation of the efficacy of the conducted therapy, all the patients underwent the Pipelle –biopsy of endometrium 1-2 months after the last injection of Buserelin-depo. As a result, it was shown that the effect of the anti-relapsing treatment of endometrial hyperplasia with Buserelin-depo in patients with uterine fibroid of small sizes with the symptoms of adenomyosis was 83-93.3% [cellular composition corresponded to the phase of menstrual cycle, or endometrial cells (endometrial atrophy) were absent in the aspirate] while the volume of uterine fibroid nodules decreased (up to 50% of the volume), and ultrasonic signs of internal endometriosis reduced. It should be noted that when using Buserelin-depo in perimenopause, the conducted therapy may coincide with the period of the onset of natural menopause, and in this case, the drug menopause smoothly goes into the physiological age menopause, thereby ensuring the relapse-free treatment. It is known that in 4 - 12 months after the end of the therapy with GnRHa a number of patients of reproductive age may experience recurrence of the symptoms, so in this age group in the end of the use of GnRHa for the purpose of suppression of the hypothalamic-pituitary-ovarian system it is advisable to conduct a stabilizing phase with the use of modern hormonal contraceptives up to the planned pregnancy or up to the menopause.
Thus, it can be stated that repeated 3-month courses of oral administration of ulipristal acetate at a dose of 10 mg once a day can effectively control bleedings and pain, reduce the volume of myomas and restore the quality of life to the level of a healthy woman for a long period of time in many patients with uterine fibroids, which is an effective and well-tolerated long-term drug treatment of this disease. On the other hand, in patients with concomitant benign uterine lesions (uterine fibroid, endometrial hyperplasia, uterine adenomyosis), an advantage of hormonal ablation influenced by Buserelin-depo is its ability not only to regress uterine fibroids but also to cause atrophic processes in endometrium, which allows us to use it in patients with combination of uterine fibroid with adenomyosis and typical endometrial hyperplasia and thereby to reduce the number of radical surgeries.
The presented material once again emphasizes the need for a differentiated approach in the treatment of patients with uterine fibroids.
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