**4. Biology of progesterone receptor antagonists ― Potentially stronger acting compounds?**

Following the discovery of the antiprogestin mifepristone, hundreds of similar compounds have been synthesized, which can be grouped in a large family of PR ligands. This family includes pure agonists, such as progesterone itself and progestins, and, at the other end of the biological spectrum, pure progesterone antagonists (PAs). An intermediate position of the spectrum is occupied by SPRMs which demonstrate mixed agonist–antagonist properties. These compounds have numerous applications in healthcare of women.

**Compound Commercial names Principal indications**

uterine leiomyomas

Uterine leiomyomas, endometriosis

Uterine leiomyomas, endometriosis

Ulipristal Ella, ellaOne, Esmya Emergency contraception,



**Table 2.** Examples of selective progesterone receptor modulators, or SPRMs, for the use in the clinical setting.

The endometrium is highly sensitive to sex steroid hormones. Estrogens cause endometrial proliferation and progesterone inhibits this growth by converting the endometrium to its secretory stage to prepare the uterus for implantation. In relation to endometrial protection, progesterone is the key inhibitor of carcinogenesis. The balance between the estrogen and progesterone activity during the menstrual cycle must be precisely maintained as an increase in the estrogen activity and/or a reduction in the antagonistic activity by progesterone will stimulate carcinogenesis. Estrogens act upon the endometrium through estrogen receptors (ERs), resulting in the induction of growth factors such as the epidermal growth factor, insulinlike growth factor-1 and growth-enhancing protooncogenes c-fos and c-myc. Besides these genomic effects of estrogens in the endometrium, estrogens exert nongenomic effects via activation of the PI3K/Akt prosurvival signaling pathway. Progesterone acts by binding to progesterone receptors (PRs), thus regulating multiple signaling pathways through PRdependent transcriptional activity. In addition to ligand-mediated regulation, PR activity is also modulated by a variety of factors including microRNAs and epigenetic factors. [38] Despite their high degree of sequence identity, the PR isoforms maintain a number of unique biological functions, including: differences in transcriptional activity, ligand response, gene regulation, and tissue-specific physiological effects. [39] Unbeneficial role of some progestins is highlighted by the finding that medroxyprogesterone acetate, a widely used and quite powerful progestin, stimulates vascular thrombin receptor *in vitro*, thus being capable of

**4. Biology of progesterone receptor antagonists ― Potentially stronger**

Following the discovery of the antiprogestin mifepristone, hundreds of similar compounds have been synthesized, which can be grouped in a large family of PR ligands. This family includes pure agonists, such as progesterone itself and progestins, and, at the other end of the biological spectrum, pure progesterone antagonists (PAs). An intermediate position of the

Asoprisnil (J867) Investigational

188 Contemporary Gynecologic Practice

Telapristone (CDB-4124) Investigational

**3. Biology of progesterone and progestins**

triggering thromboembolic events. [40, 41]

**acting compounds?**

Most PAs and SPRMs display direct antiproliferative effects in the endometrium when given orally, although with variable strength being compound- and dose-dependent. PAs can also be released using an IUS and induce endometrial atrophy in nonhuman primates. PAs and SPRMs have two important effects in primates: 1) they suppress endometrial growth by blocking the action of progesterone on endometrial progestational development and conse‐ quently induce amenorrhea; and 2) they suppress the proliferative effects of estrogen on endometrial proliferation and prevent unopposed action on this tissue. [42] These properties indicate the potential for clinical applications of these compounds which cover a broad field and are very promising in major public health areas. These include emergency contraception, long-term estrogen-free contraception (administered alone, or in association with a progestinonly pill to improve bleeding patterns), uterine leiomyomas (where they induce a marked reduction in tumor volume and produce amenorrhea) and endometriosis. Further develop‐ ments might also include the treatment of hormone-dependent tumors. [43, 44]
