HPE HPE 85 – Spring 2017 - Page 55

Practical therapeutics Issue 85 | Spring 2017 evidence was insufficient to support the use of progestogens or progestogen- releasing intrauterine systems in treating pre-menopausal women with uterine fibroids. 15 Overall, fibroids are associated with increased rates of discontinuation of the LNG-IUS, difficulties at the time of fitting and higher device expulsion rates. The IUS also acts as a contraceptive and therefore not an option for women wishing to conceive. Gonadotropin-releasing hormone (GnRH) analogues GnRH agonists are synthetic analogues of GnRH that after an initial flare effect, inhibit the hypothalamic–pituitary– ovarian axis. The resulting drop in circulating oestrogen levels is associated with fibroid degeneration, resulting in shrinkage of the fibroid. GnRH agonists have been mainly used for the treatment of fibroids in perimenopausal women or as a pre-operative treatment for three to four months. Evidence There is strong evidence that if given three to four months before myomectomy or hysterectomy, GnRH agonists are associated with reduced fibroid volume, correction of pre-operative anaemia, reduction in intraoperative blood loss, reduced midline incisions and increased vaginal approach to surgery where appropriate. 23,24 However the reduction in fibroid size and symptoms is usually temporary and the fibroids often re-grow to pre-treatment size after cessation of GnRH agonists in most women. The risk of fibroid recurrence after a course of GnRH agonists in patients who have subsequently undergone myomectomy is controversial and there are limited data to confirm the association. 25–27 GnRH agonists are associated with side effects such as hot flushes, sleep disturbances, vaginal dryness, low mood and loss of bone mass after prolonged use. Various therapies have been studied as add-back (combined oestrogen and progestin, medroxyprogesterone acetate, tibolone) to reduce such adverse effects to allow longer use of GnRH agonists. 27 GnRH antagonists have not been studied in as much detail as the agonists. These agents cause reduction in fibroid volume, but their use is limited by their shorter half life, which necessitates daily administration, and that there are few oral preparations. 10 Progesterone receptor modulators (PRMs) Since the emergence of mifepristone (RU-486), the first progesterone receptor (PR) antagonist, more than 25 years ago, many steroidal, as well as non-steroidal, compounds displaying progesterone antagonist or mixed agonist/antagonist activity have been synthesised. Collectively, they are known as PRMs. Progesterone receptors are present in higher concentrations in fibroids than in normal myometrium and some of the PRMs that have been the subject of recent clinical trials or research studies in relation to fibroids treatment include mifepristone, CDB-4124 (telapristone), CP-8947 and J867 (asoprisnil) and CDB-2914 (ulipristal acetate). The following mechanisms of action have been proposed for the effect of PRMs on fibroids: • Ulipristal downregulates the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and their receptors in cultured fibroid cells 28 resulting in suppression of neovascularisation, cell proliferation and survival. 29 • Ulipristal and asoprisnil inhibit proliferation of cultured fibroid cells and induce apoptosis by upregulating cleaved caspase 3 and downregulating Bcl-2. 28–30 • Ulipristal also increases the expression of G&WF&FV6W22@FV7&V6W2W&W76bF77VR憖&F"`WF&FV6W2D2@6vV27VGW&VBf'&B6V2"FW 'FB7F2b$26VFP憖&Fbז6V&ƖfW&F&VGV7FWG&6VV"G&T4Ґ6VB&GV7FBGVF`FR&Fb&vW7FW&R&V6WF 6f&27VGW&VBז6V23֖fW&7FRB6&6fR6&VV766FVBvFFV7&V6RWFW&P'FW'&Bfr V&W"b6Ɩ6G&2fPW7F&Ɨ6VBFRFVFb$2FPG&VFVBbWFW&Rf'&G2FW&P766FVBvF&VGV7F&VVFr6Rbf'&G2BfW&&fVVBVƗGbƖfRVƖPr7Frv$wVW2FWF@fRFRG&v&62bFR&fV@W7G&vVFVf6V7BFV7&V6R&P֖W&FV6G֖fW&7FR%RCb֖fW&7FRv2G&GV6VB2G'VpW6VBf"VF6FW&֖F`&Vv7vF"vFWB֗6&7F֖fW&7FR2F&vW7FvFvffGf"&vW7FW&R&V6WF'2WfFV6PV&ǒ&W'G2bFRW6Rb֖fW&7FPf"FRG&VFVBbf'&G2FFR&6F#"vVFRVWBW6VBF6W0&vrg&"RFSrFǒ@&W'FVB&VGV7FWFW&Rf'&@fVRbC( 3SRvFV'&V7B7V&V7G23"F2&W'Bv06'&&&FVB'W"V"FW"g&Цw&WvW6VB֖fW&7FRBF6PbR"rW"Ff"RV"@fVBFBBv2VffV7FfRFV7&V6pVWFW&RfVR'SRvPV'&V67W'&VBC( 3sRbFP7V&V7G232GfW'6RVffV7G26VFV@f6F"7F2'WB6vR&R֖W&FV6Gv2FVB6PVFWG&W'6v2FVB#RbFRvV32FW6R&W'G2vW&PfvVB'$5BFRW6R`֖fW&7FRf"FRG&VFVBbWFW&Pf'&G2F2v2FV&R&ƖB6V&6G&VB7GVGbC"vVfW"W&Bb6F23BBFRWF'0&W'FVB6vf6Fǒ&fVBfW&VƗGbƖfRV֖&FW2B&VGV6V@WFW&RfVW2FW"$5BvVvW&R76vVBF֖fW&7FRP"rFǒf"F&VRF2vFWB6V&w&WvF&FF6W2FW&PvW&RWVfVB&VGV7F2f'&B@WFW&RfVW2B7FF0&fVVG23P77FVF2&WfWrv26GV7FVBFFWFW&֖RFRVff67B6fWG`֖fW&7FRf"FRvVVB`WFW&Rf'&G2&RVW6vV3bF&VRG&2ffr 'F6G2vW&R6VFVB6&6খFW'fVF26VFVBFffW&VBF6vW0b֖fW&7FR6V&BfF֖ F&WG2FW&R2WfFV6RFBG&VFV@vF֖fW&7FR&VƖWfW2VgV7G'V&VVFr6&VBvF6V&FW&Rv2WfFV6RbVffV7Bb֖fW&7FRFRf'&@fVRFRVBFF7VvvW7FVBখ7&V6VBGfW'6RWfVB&&VFWG&7FwFP֖fW&7FRw&W6&VBvF6V&"3cSRR4B>( 0#r3R3bFRWF'266VFVBF@֖fW&7FR&VGV6VBVgV7G'V&VVFrB&fVBf'&B7V6f0VƗGbƖfRvWfW"Bv2BfV@F&VGV6Rf'&BfVRFW7FRFR&VVf6VffV7G2`֖fW&7FRFRVFWG&W'66VV6RvVƖ֗G2FRW6RbF07F&7WW&R6УS