Ulipristal Acetate Modulates the Expression and Functions of Activin A in Leiomyoma Cells

Ciarmela, Pasquapina; Carrarelli, Patrizia; Islam, Soriful; Janjusevic, Milijana; Zupi, Errico; Tosti, Claudia; Castellucci, Mario; Petraglia, Felice

doi:10.1177/1933719114542019

Cited by 33 publications

(26 citation statements)

References 51 publications

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“…An in vitro study demonstrated another possible mechanism of action of UPA: inhibition of activin A expression and function in cultured leiomyoma cells ( Ciarmela et al ., 2014 ).…”

Section: The Future Of Medical Therapymentioning

confidence: 99%

Uterine fibroid management: from the present to the future

Donnez

Dolmans

2016

Hum. Reprod. Update

538

506

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Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications.Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid ‘radical’ surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids.There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention.There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies.The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.

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“…An in vitro study demonstrated another possible mechanism of action of UPA: inhibition of activin A expression and function in cultured leiomyoma cells ( Ciarmela et al ., 2014 ).…”

Section: The Future Of Medical Therapymentioning

confidence: 99%

Uterine fibroid management: from the present to the future

Donnez

Dolmans

2016

Hum. Reprod. Update

538

506

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“…It also decreases activin binding proteins, follistatin, activin receptor type (ActRIIB), and activin receptor-like kinase 4 (Alk4) mRNA expressions. In addition, it was able to block the activin A-induced increase in fibronectin or VEGF-A mRNA expression [ 101 ]. Moreover, ECM deposition in UF is also reduced by UPA due to increasing both matrix metalloproteinases (MMPs) and ECM metalloproteinase inducer (EMMPRIN) while reducing tissue inhibitor of metalloproteinases (TIMPs) [ 100 , 102 ].…”

Section: Treatment Options For Uterine Fibroidsmentioning

confidence: 99%

“…Moreover, ECM deposition in UF is also reduced by UPA due to increasing both matrix metalloproteinases (MMPs) and ECM metalloproteinase inducer (EMMPRIN) while reducing tissue inhibitor of metalloproteinases (TIMPs) [ 100 , 102 ]. Finally, UPA also increases the ratio of progesterone receptor isoforms (PR-A/PR-B) as it decreases PR-B receptor expression while increases PR-A so UPA inhibits progesterone-mediated effects on fibroid cells [ 98 – 101 , 103 – 108 ]. Figure 4 summarizes UPA mechanisms of action presented in the literature so far.…”

Section: Treatment Options For Uterine Fibroidsmentioning

confidence: 99%

Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids†

Ali

Al-Hendy

2017

Biology of Reproduction

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Uterine fibroids (UFs, AKA leiomyoma) are the most important benign neoplastic threat to women's health, with costs up to hundreds of billions of health care dollars worldwide. Uterine fibroids caused morbidities exert a tremendous health toll, impacting the quality of life of women of all ethnicities, especially women of color. Clinical presentations include heavy vaginal bleeding, pelvic pain, bulk symptoms, subfertility, and obstetric complications. Current management strategies heavily lean toward surgical procedures; nonetheless, the choice of treatment is generally subject to patient's age and her desire to preserve future fertility. Women with UF who desire to maintain future fertility potential face a dilemma because of the limited treatment choices that are currently available to help them achieve that goal. Recently, ulipristal acetate the first of the promising family of oral selective progesterone receptor modulators has been approved for UF treatment in Europe, Canada, and several other countries and is under review for possible approval in the USA. In this review article, we discuss recent advances in the management options against UF with a bend toward oral effective long-term treatment alternatives who are particularly suited for those seeking to preserve their future fertility potential. We also explore the transformative concept of primary and secondary UF prevention using these new anti-UF agents. We envision a remarkable shift in the management of UF in future years from surgical/invasive treatment to orally administrated options; clearly, this potential shift will require additional intense clinical research.

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“…2012 ). Ulipristal was shown to block the expression of fibronectin and VEGFA mRNA induced by activin A in cultured leiomyoma cells, thus blocking cell growth ( Ciarmela et al . 2014 ) and the substantial angiogenesis required by these tumors to proliferate ( Xu et al .…”

Section: Mechanisms Of Growth Inhibition Driven By Antiprogestinsmentioning

confidence: 99%

Antiprogestins in gynecological diseases

Goyeneche

Telleria

2015

Reproduction

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Antiprogestins constitute a group of compounds, developed since the early 1980s, that bind progesterone receptors (PR) with different affinities. The first clinical uses for antiprogestins were in reproductive medicine: e.g. menstrual regulation, emergency contraception, and termination of early pregnancies. These initial applications, however, belied the capacity for these compounds to interfere with cell growth. Within the context of gynaecological diseases, antiprogestins can block the growth of and kill gynaecological-related cancer cells, such as those originating in the breast, ovary, endometrium, and cervix. They also can interrupt the excessive growth of cells giving rise to benign gynaecological diseases such as endometriosis and leiomyomata (uterine fibroids). In this article, we present a review of the literature providing support for the anti-growth activity antiprogestins command over cells from various gynaecological diseases. We also provide a summary of the cellular and molecular mechanisms reported for these compounds that lead to cell growth-inhibition and death. The preclinical knowledge gained during the past few years provides robust evidence to encourage using antiprogestins in order to alleviate the burden of gynaecological diseases, either as monotherapies or as adjuvants of other therapies with the perspective of allowing for long-term treatments with tolerable side effects. The key to the clinical success of antiprogestins in this field, likely lies in selecting those patients who will benefit from this therapy. This can be achieved by defining the genetic makeup required—within each particular gynaecological disease—for attaining an objective response to antiprogestin-driven growth-inhibition therapy.

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Ulipristal Acetate Modulates the Expression and Functions of Activin A in Leiomyoma Cells

Cited by 33 publications

References 51 publications

Uterine fibroid management: from the present to the future

Uterine fibroid management: from the present to the future

Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids†

Antiprogestins in gynecological diseases

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