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Asoprisnil: a Selective Progesterone Receptor Modulator

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Asoprisnil: a Selective Progesterone Receptor Modulator Molecules of the Millennium Asoprisnil: A selective progesterone receptor modulator Progesterone is a hormone that is secreted by the corpus agonist–antagonist at progesterone receptors. Asoprisnil has luteum, placenta, and in minimal quantities by the testis and an antagonistic effect on the endometrium, ovary, and breast adrenal cortex. The important function of progesterone is to tissue. It has no effect or partial agonistic effect on myometrium sustain pregnancy. Large doses of progesterone inhibit LH of pregnant uterus, whereas in myometrium of leiomyoma it surge and potentiate the inhibitory effect of estrogen on acts as an antagonist. hypothalamus–pituitary axis, preventing ovulation. Therefore, On endometrium synthetic substances which are agonist at progesterone The selective progesterone receptor modulators cause receptor called “progestins” were developed, and these atrophy of the endometrium. Both selective progesterone substances became an essential constituent of oral receptor modulators and progesterone antagonists make the contraceptive pills. Progestins are mitogenic for breast blood vessels that supply blood to the endometrium robust, epithelium and increase mammographic shadow. Clinical trials whereas they become fragile with progestins. Both have shown that progestins and estrogens, and not estrogen progesterone antagonists and SPRMs cause amenorrhea. But alone, cause an increased incidence of breast cancer in the way in which both these group of drugs cause amenorrhea postmenopausal women.[1,2] Progesterone receptor is different. The Progesterone antagonists cause amenorrhea antagonist,mifepristone was then developed, which is now used by causing anovulation, whereas the SPRMs have a direct for post-coital contraception and termination of early inhibitory effect on endometrium. pregnancy. There was a constant need for a drug with the On ovary beneficial effects of progestins and progesterone antagonists, The most important aspect of selective progesterone and at the same time will not affect the estrogen secretion, receptor modulators on the ovary is that they do not affect the thereby retaining the protective effect of estrogen on the bone estrogen secretion from ovary. So the beneficial effects of and cardiovascular system .This necessity led to the discovery estrogen on the bone and cardiovascular system are well of a new group of partial agonist–antagonist at the maintained. Also, they have no or minimal inhibitory effect on progesterone receptor called the “selective progesterone the ovarian progesterone secretion. The progestins and receptor modulators” [SPRMs]. These drugs are also known progesterone antagonists inhibit ovulation, whereas the as “mesoprogestins”. Asoprisnil is the first selective selective progesterone receptor modulators may only partially progesterone receptor modulator. inhibit it. Mechanism of tissue selectivity On pregnant uterus Another advantageous effect of SPRMs is that they do not Progestins, progesterone antagonists, and SPRMs all act affect the myometrial contractility of the pregnant uterus. They through the Progesterone receptor (PR). The PR exists as two do not also affect the cervix of the pregnant uterus. This is in isoforms – PR-A and PR-B. These isoforms play different roles strong contrast to the progesterone antagonists which are used depending on the tissue where it is present. PR-A decreases for termination of early pregnancy. estradiol responsiveness in the tissues. PR-B is responsible On breast for the proliferation of endometrium, differentiation and As already discussed, the progestins have a drawback of proliferation of breast tissue. increasing the proliferation of the epithelium of breast. This Generally, PR exists in the DNA non-binding state. When effect is not seen with selective progesterone receptor progestins/progesterone antagonists/SPRMs bind to PR, it modulators which decrease the proliferation of breast tissue. undergoes dimerization and a conformational change, thereby converting it into a DNA-binding form. This form binds to Pharmacokinetics progesterone response elements (PRE) present in DNA of the Asoprisnil is given orally in a dose range of 5 to 25 mg target tissue. This receptor-DNA complex recruits molecules once daily. It is well absorbed orally. It is metabolised in the which regulate transcription known as co-regulators. Co- liver by the cytochrome P450 enzymes. The metabolite is found regulators may either be co-activators which activate to have weaker agonist and stronger antagonist effects than transcription, or co-repressors which inhibit transcription.[3] asoprisnil. But its exact role in the pharmacological effect of The agonist-receptor-DNA complex will recruit co-activators asoprisnil is still not known. The elimination half-life of and the antagonist-receptor-DNA complex will recruit co- asoprisnil is 4-5 h.[5] repressors. The tissue selective actions of the SPRMs depend on the relative concentrations of co-activators and co- Uses repressors in the target tissue.[4] Transcription activation leads Uterine fibroids to protein synthesis and subsequent effects on the target tissue. Uterine fibroids (leiomyoma) are the most common benign Pharmacological actions tumour in females. In the past, estrogen was considered to Selective progesterone receptor modulators are partial play an important role in the growth of myomas. But now 266 Indian J Pharmacol | August 2005 | Vol 37 | Issue 4 | 266-267 Asoprisnil studies have shown that there is an increased concentration The results of phase III trials in patients with menorrhagia of progesterone receptors in leiomyoma tissue than the normal associated with uterine fibroids are awaited. myometrium.[6] Two randomized controlled trials have shown A randomized placebo-controlled, dose-finding phase II trial that progestins when used as add-back therapy in combination was done with asoprisnil in subjects with a laparoscopic with GnRH agonists, attenuate or reverse the inhibitory effects diagnosis of endometriosis, exhibiting moderate or severe pain. of GnRH agonists on leiomyoma.[7,8] On the basis of these Asoprisnil was given in doses of 5, 10 and 25 mg for 12 weeks. evidences, and on the fact that asoprisnil is a progesterone There was a considerable reduction in the average daily antagonist at uterine myometrium, it is used in the treatment combined scores of non-menstrual pelvic pain and of uterine fibroids in the dose range of 5 to 25 mg/day. Phase dysmenorrhea in all dose regimens compared with placebo. II trials have shown promising results and phase III trials are No serious drug-related adverse events were reported.[5] underway. Conclusion Endometriosis Asoprisnil is the first drug of the novel group – the selective Endometriosis is a disease that is characterized by the progesterone receptor modulators. It is a partial agonist– presence of functional endometrial tissue outside the uterus. antagonist that has the advantages of both the progestins and The main presenting features are pelvic pain and infertility. progesterone antagonists while retaining the beneficial effect The medical management of pain involves progestins in the of estrogen on the bone and cardiovascular system. Phase III form of oral contraceptive pills, androgenic progestins like clinical trials are underway to study its use in treating uterine danazol and GnRH agonists. But on chronic use, these have leiomyoma and endometriosis. It is premature to conclude undesirable side effects such as hypoestrogenic state (GnRH anything at this time, and watchful waiting is needed to see agonists), acne, hirsutism and voice change (Danazol). Because whether this group of drugs comes up as a promising medical asoprisnil inhibits endometrial proliferation without therapy for uterine leiomyoma and endometriosis. compromising the systemic beneficial effects of estrogen, it has the potential to become the favored medical treatment for C. Girish, M. Jayanthi, G. Sivaraman endometriosis. Department of Pharmacology, Side effects Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry- 605 006. Asoprisnil is generally well tolerated in a dose of 5-25 mg. E- mail: [email protected] Minor side effects such as headache and abdominal pain were References reported and were self-limiting. There has been no report of 1. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stamper MJ, [9] any drug-related serious adverse effects. As the drug is still et al.The use of estrogens and progestins and the risk of breast cancer in post undergoing phase III trials, the ongoing trials and vigorous menopausal women. N Engl J Med 1995;332:1589-93. post- marketing surveillance can bring out any adverse effect, 2. Rossouw JE, Anderson GL, Prentice RL, Lacroix AZ, Kooperberg C, Stefanick which is not known now. ML, et al. Risks and benefits of estrogen plus progestin in healthy post menopausal women: Principal results from the Women’s Health Initiative Clinical trials randomized controlled trial. JAMA 2002;288:321-33. 3. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear In a double blind dose escalation study, Chwalisz K, et al. receptor coactivators and corepressors. Mol Endocrinol 1996;10:1167-77. evaluated the effects of asoprisnil in 60 regularly cycling 4. Smith CL, O’Malley BW. Coregulator function: A key to understanding tissue premenopausal women at doses ranging from 5 to 100 mg/ specificity of selective receptor modulator. Endocr Rev 2004;25:45-71. day for 28 days. Asoprisnil
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