**8. References**

172 Endometriosis - Basic Concepts and Current Research Trends

demonstrated a reduction in myoma volume and uterine bleeding with asoprisnil and RU-486 (Chabbert-Buffet et al., 2005; DeManno et al., 2003; Fiscella et al., 2006). Larger studies have been completed for asoprisnil. In one randomized, controlled trial, 129 women with at least 1 fibroid greater than 3 cm in diameter or a uterine volume twice the normal (>200 cm3) were treated for up to 3 months with asoprisnil (5, 10, or 25 mg) or placebo (Chwalisz et al., 2007). Significant reduction in uterine fibroid volume was noted by week 4 and persisted

Fig. 3. Effect of escalating multiple dose of PF-02413873 on endometrial thickness (mm) (a) and the mid cycle LH surge (mIU/mL) (b) in healthy women compared with placebo (Howe

There are compelling pre-clinical and clinical evidence to suggest that as well as directly antagonising the effect of progesterone, PRAs also functionally antagonise the effects of estrogen on the endometrium. This coupled with the suppression of ovarian folliculogenesis induces anovulatory amenorrhoea. Evaluation of the PR axis in animal models of endometriosis has suggested that PRAs can suppress the growth of ectopic endometriotic lesions. The mechanism driving this effect is still not clear, but it sufficient to maintain ovarian activity and estradiol levels adequately to protect bone as well as other potential post-menopausal symptoms more commonly encountered with ovarian suppression. In women with endometriosis, the data available from small clinical evaluations, strongly suggest that PRA treatment reduces disease symptoms, whilst maintaining normal levels of bone mineral density. Further clinical evaluation in larger randomised, placebo controlled and blinded studies are warranted, both to underscore the clinical benefit as well as understand the safety of the mechanism compared with existing standard of care therapy (endometrial, cardiovascular and bone safety, in particular). The medicinal chemistry challenge in designing potent, selective and safe PRAs is not inconsiderable, especially given the large number of examples whose clinical development have been curtailed (e.g. onapristone, PF-02413873, asoprisnil). However, the clinical evidence observed so far provides strong confidence that the class could have utility as a chronic treatment for endometriosis as well as a range of other gynaecological indications and malignant

through the end of the study in a dose-dependent fashion.

**a b**

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**10** 

*Italy* 

**Endometriosis and Angiogenic Factors** 

*Department of Gynecology and Obstetrics University of Pisa, Pisa,* 

P. G. Artini, M. Ruggiero, F. Papini, G. Simi, V. Cela and A. R. Genazzani

Little is known about the pathogenesis of endometriosis. The prevailing hypothesis is that following retrograde menstruation, uterine endometrial tissue attaches, invades the

The development of new blood vessels represents a crucial step during the establishment of endometriosis because endometriotic implants require neovascularization to guarantee oxygen and essential nutrient supply (Groothuis et al., 2005; McLaren, 2000). The interaction between the ectopic endometrium and the peritoneal tissue is a prerequisite for the

At least, three processes appear to be critical to the establishment of endometriosis, according to the implantation theory: invasiveness, tissue remodeling and interactions between the ectopic endometrium and the surrounding peritoneal tissues (Giudice et al.,

The establishment of endometriotic lesions needs a cascade of neoangiogenic factor, like the vasculatr endothelial factor, cytokines and metalloproteinases: this complex interrelation between factors permit sprouting of capillaries from pre-existing vessels and the subsequent

Vascular endothelial growth factors are important signaling proteins involved in both vasculogenesis (the *de novo* formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). VEGF family comprises seven members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PlGF. All members have a common VEGF homology domain. This core region is composed of a cystine knot motif, with eight invariant cysteine residues involved in inter- and intramolecular disulfide bonds at one end of a conserved central four-stranded-sheet within each monomer, which

The human *VEGF* gene (*VEGFA*, OMIM 192240) is located on chromosome 6p12 (Zhao Z, et

**1. Introduction** 

2008).

al 2008).

peritoneal surface, and becomes vascularized.

induction of angiogenesis and the maintenance of endometriosis

supply for the development of ectopic implants (Hyder and Stancel, 1999).

dimerize in an antiparallel, side-by-side orientation (Neufeld G, wt al 1999).

**2. Vascular endothelial growth factors family 2.1 Vascular Endothelial Growth Factor(VEGF)** 

**2.1.1 VEGF family and its receptors** 

