Journal of Gynecology and Neonatal Biology

Leiomyomas are the common benign tumours of uterus. Surgery is the most common mode of treatment of symptomatic fibroids. With the advent of minimally invasive interventional procedures like uterine artery embolization (UAE), and focused ultrasound on MRI we got some lesser invasive techniques, although they have drawbacks regarding ovarian reserve etc for patients desiring fertility. Initially GnRH agonists like leuprolide acetate were the most effective medical agents introduced, but their drawback was bone density demineralization, hot flushes on long term use besides cost. Selective progesterone receptor modulators gradually got introduced with initial trials with mifepristone (RU486), followed by asoprisnil, ulipristalacetate. Since mifepristone had antiglucocorticoid and androgen receptor activity it was not approved by FDA for license, while four PEARL trials have got completed for UPA acetate 5&10mg regarding safety and efficacy and intermittent therapy with 5mg got FDA approval in Europe and Canada before surgery. Further trials indicated it may be the future drug of choice for patients desiring fertility for long term intermittent therapy and possibly avoiding surgery and its complications like adhesions, uterine scar and risk for rupture during pregnancy. However in countries where uripristal is not available still one is forced to use mifepristone. Detailed mechanism of all these drugs is discussed and a case report of a young unmarried girl with high BMI is reported where mifepristone intermittent was effective not only in relieving patients symptoms but effective in decreasing uterine and fibroid volume which highlights how in such young cases one can preserve future fertility without putting them at risk of surgery and sometimes myomectomy complications ending in hysterectomy. *Corresponding Author: Kulvinder, K.K. Department of Obstetrics and Gynecology, Centre for Human Reproduction, G.T.B. Nagar, Jalandhar-144001, Punjab, India. Tel: 91-181-9513508180; E-mail: [email protected] Citation: Kulvinder, K.K. et al. Medical Management of Leipmyomas-Emphasis for Different Geographical Regions (2015) J Gynecol Neonatal Biol 1(3): 18. J Gynecol Neonatal Biol | Volume 1: Issue 3 Introduction Uterine leiomyoma (UL) are the most common benign soft tissue tumours in women occurring in 20-40% of women of reproductive age[1], and frequently cause excessive uterine bleeding, chronic pelvic pain/pressure and dyspareunia). UL are believed to derive from the transformation of myometrial smooth muscle cell, connective tissue fibroblast[2]. Surgery in the form of total abdominal hysterectomy (TAH), myomectomy/ robotic assisted TAH/myomectomy used to be performed for one third of symptomatic fibroids (pelvic pain, heavy menstrual bleed, rapidly growing masses[1,3,4]. Injury to bowel, bladder, blood vessels becomes the leading cause for post surgical scar formation mediated by proinflammatory/profibrotic mediators at injury site. Recently nonsurgical minimally invasive interventional procedures like uterine artery embolization (UAE) where emboli occlude uterine artery which disrupts blood supply to fibroid or ii)Magnetic resonance image guided focused ultrasound to reduce leiomyoma volume have come in vogue[5,6]. MRI guided focused ultrasound is effective only for large myomas, while particulate used in UAE and excessive cellular damage following conclusion of MRI leave debris and cellular fragments in uterus which can cause tissue reactivity and other symptoms of UAE like pulmonary emboli make them unsuitable for patients desiring fertility. Medical Management Initially long acting GnRH agonists therapies with doses as high as 11.75 mg, which act through pituitary–ovarian axis and create a hypoestrogenic condition have proven effective in reduction of fibroids although they don’t work in all patients and drawback is bone density deminKulvinder Kochar Kaur1*, Gautam Allahbadia2 Received date: June 30, 2015 Accepted date: September 15, 2015 Published date: September 22, 2015 Case Report Medical Management of Leiomyoma-Emphasis for Different Geographical Regions DOI: 10.15436/2380-5595.15.010 1 Copy rights: ©2015 Kulvinder, K.K. This is an Open access article distributed under the terms of Creative Commons Attribution 4.0 International License. Kulvinder, K.K. et al. 2 eralization with long term use, hot flushes and recurrence after stoppage of therapy besides cost factor. Although add back therapy takes care of the hypoestrogenic side effects further selective estrogen receptor modulators (SERM) like raloxiphene and tamoxiphene[7-9] and selective progesterone receptor modulators (SPRM) like CDB2814 (ulipristal acetate), CDB 4124, asoprisnil (J865) and RU486 (Mifepristone) underwent trials. Although uripristal acetate (UPA) has received approval after several therapeutic multicentric trials and is available in many western and European countries, it is still not available in developing countries like India and the basic aim of this review is to highlight the importance of using a SPRM agent prior to surgery to avoid or make it easier and offer an alternative to surgery and highlight the advantages and disadvantages of surgery in patients desiring fertility and how use of UPA prior to hysteroscopy if must, may decrease the morbidity of surgery and decrease the chances of a laparotomy to a laparoscopy and make hysteroscopy a single step from two step process and in countries like India where no UPA available alternative of using mifepristone is discussed. Further since after stoppage of medical treatment fibroids recur strategies to develop newer therapies which would prove to be permanent and without side effects is discussed based on the knowledge of ongoing research for development of effective medical agents. Mechanism of Action Animal studies done by Varghese et al have shown that REI silencing transcription factor (REST), A silencer or transcriptional repressor results in the expression of G-protein coupled receptor10 (GPR10) which when activated promotes PI3K-Akt/Mtor/rapamycin pathway and cell proliferation[10,11] (Fig1). Although somatic mutations of MED12 a product of the mediator complex subunit 12 gene and present on exon 2 are present in 30-70% of cases of leiomyomas[12-14] ,Varghese et al didn’t find any altered interaction between REST and MED12. Figure 1: Courtesy ref no 11 Loss of REI silencing transcription factor(REST)in patient leiomyoma cells resulted in the expression of the G protein coupled receptor 10(GPR10)and Akt/MTOR/ signalling pathway. Transgenic overexpression of GPR10 in mouse myometrial smooth muscle cells resulted in a phenotype characteristic of human fibroid tissue. GnRH agonists act at the level of P-O axis to cause regression of leiomyoma growth however direct action on peripheral tissues including uterus by acting on GnRH receptors is also documented. They act directly on cell growth and apoptosis in myometrial and leiomyoma cells. Because gonadal hormones induce or maintain UL growth SPRM‘s have been evaluated as therapeutic agents. The concept that progesterone (Pg) plays a vital role in the growth of uterine leiomyomata is supported by the wealth of accumulating data from various studies. Effects of Pg on target tissues are mediated by the Pg receptor (PR) which belongs to the nuclear receptor family. PR functions as a ligand activated transcriptional factor to regulate the expression of target genes. PR exists in two isoforms PRA and PRB, which are transcribed from two promoters on a single gene[15,16]. Although PRB functions as a transcriptional activator of Pg responsive genes, PRA may function as a transcriptional inhibitor[17,18]. Several studies have demonstrated that PR is upregulated in uterine leiomyomata, as compared with adjacent normal myometrium[19] at mRNA and protein levels. Evidence from clinical studies suggests that synthetic progestins stimulate leiomyoma growth[20]. Selective progesterone receptor modulators (SPRM) are a novel class of Pg receptor ligands exhibiting mixed and/or partial agonist/antagonist activity. Mifepristone was the first SPRM developed in 1981, which is a synthetic C19 nonsteroid with a potent antagonist of PR[21], but also simultaneous glucocorticoid receptor (GR) and androgen receptor(AR) activity. When given for 3-6 months, mifepristone reduced UL size and symptoms and induced amenorrhoea in 63100%of women[22]. Mifepristone induces a significant decrease in uterine volume, a significant reduction in Pg receptors content without affecting the estrogen receptor level[8,23]. Under in vivo conditions RU486 also altered the rate of DNA synthesis and growth factors and proteases expression in MSMC or LSMC primary cultures[8]. 17 β-estradiol inhibited whereas Medroxyprogesterone acetate (MPA) enhanced the expression of miR 21 and miR 26 a in MSMC and LSMC respectively, and the expression of miRNAs was also the target of ICI 182780 and RU486 respectively[24]. GnRH and RU486 therapies often cause UL regression possibly by enhancing cellular apoptosis[25,26]. Although initially it was used in low doses by Fiscella et al, a dose of 50mg alternate day was found to be more effective for greater reduction of myoma as well as uterine volume by RU486[27,28]. Further Engman et al studied Glutathione-s transferase mu1 (GSTM1) gene pathway as a biomarker for which patients would be good responders to mifepristone, or poor responders with those having high expression of GSTM1 as good responders and this can be used to predict the leiomyoma volume regression in response to mifepristone treatment[29]. Role of Asoprisnil Asoprisnil (J867) is the first SPRM that has been clinically evaluated in patients of symptomatic uterine fibroids and endometriosis[30,31]. Asoprisnil (As) is a 11β benzaldoxime substituted steroidal SPRM that shows high uterine selectivity[32]. Previously conducted studies have shown that asoprisnil reversibly suppresses uterine bleeding, primarily targeting uterine endometrium[33]. Further studies have demonstrated that asoprisnil reduces volume of uterine fibroids in a dose dependent manner[30]. Similarly in vitro studies have shown Asoprisnil (As) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in absence of similar effect in myomeJ Gynecol Neonatal Biol | Volume 1: Issue 3 www.ommegaonline.org Management of Leiomyomas-Emphasis