telapristone-acetate and ulipristal-acetate

Uterine fibroids are common in women of reproductive age and can have a significant impact on quality of life and fertility. Although a number of international obstetrics/gynecology societies have issued evidence-based clinical practice guidelines for the management of symptomatic uterine fibroids, many of these guidelines do not yet reflect the most recent clinical evidence and approved indication for one of the key medical management options: the selective progesterone receptor modulator class. This article aims to share the clinical experience gained with selective progesterone receptor modulators in Europe and Canada by reviewing the historical development of selective progesterone receptor modulators, current best practices for selective progesterone receptor modulator use based on available data, and potential future uses for selective progesterone receptor modulators in uterine fibroids and other gynecologic conditions.

Topics: Contraceptive Agents, Female; Disease Management; Estrenes; Female; Forecasting; Humans; Leiomyoma; Mifepristone; Norpregnadienes; Oximes; Population Growth; Receptors, Progesterone; Steroids; Uterine Neoplasms

Fibroids are the most common tumor of the female reproductive tract, but approved medical treatments are limited. Patients demand uterine-sparing treatments which preserve fertility and avoid surgery. We systematically reviewed PubMed and Cochrane databases from January 1985 to November 2015 for evidence-based medical therapies for fibroids in the context of disease prevention, treatment of early disease, treatment of symptomatic disease, and preoperative management. We identified 2182 studies, of which 52 studies met inclusion and exclusion criteria. Published data affirm the efficacy of multiple agents, which are promising avenues for the development of medical alternatives to surgery.

Topics: Androgens; Aromatase Inhibitors; Contraceptive Agents, Female; Contraceptives, Oral, Combined; Curcumin; Delayed-Action Preparations; Drugs, Chinese Herbal; Estradiol; Estrenes; Estrogen Receptor Antagonists; Evidence-Based Medicine; Female; Fulvestrant; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Intrauterine Devices, Medicated; Leiomyoma; Levonorgestrel; Medroxyprogesterone Acetate; Mifepristone; Neoadjuvant Therapy; Norpregnadienes; Oximes; Plant Extracts; Receptors, Progesterone; Selective Estrogen Receptor Modulators; Tea; Uterine Myomectomy; Uterine Neoplasms; Vitamin D; Vitamins

The majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolisation or focussed ultrasound surgery). None of these treatments is a panacea, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age. It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids and this has raised the possibility that anti-progestins and (PRMs) could be useful in the medical management of fibroids. Some of the compounds which have produced promising results in recent clinical trials or research studies include mifepristone, CDB-4124 (telapristone), CP-8947, J-867 (asoprisnil) and CDB-2914 (ulipristal acetate or UA). UA has recently completed Phase III clinical trials with very encouraging results, and has now acquired a licence for clinical use in Europe. While considerable research has yet to be done on the long-term safety and efficacy of UA there is nevertheless good reason for optimism on the emergence of effective medical therapy in the form of UA and possibly other PRMs.

Topics: Endometrium; Estrenes; Female; Hormone Antagonists; Humans; Hyperplasia; Intrauterine Devices, Medicated; Leiomyoma; Levonorgestrel; Mifepristone; Norpregnadienes; Oximes; Receptors, Progesterone

Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.

Topics: Animals; BRCA1 Protein; Breast Neoplasms; Carcinogenesis; Disease Models, Animal; Epithelial Cells; Female; Humans; Mammary Glands, Animal; Mastectomy; Mice; Mifepristone; Norpregnadienes; Receptors, Progesterone; Stromal Cells; Tumor Microenvironment