Selective progesterone receptor modulator

WikiDoc Resources for Selective progesterone receptor modulator

Articles

Most recent articles on Selective progesterone receptor modulator

Most cited articles on Selective progesterone receptor modulator

Review articles on Selective progesterone receptor modulator

Articles on Selective progesterone receptor modulator in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Selective progesterone receptor modulator

Images of Selective progesterone receptor modulator

Photos of Selective progesterone receptor modulator

Podcasts & MP3s on Selective progesterone receptor modulator

Videos on Selective progesterone receptor modulator

Evidence Based Medicine

Cochrane Collaboration on Selective progesterone receptor modulator

Bandolier on Selective progesterone receptor modulator

TRIP on Selective progesterone receptor modulator

Clinical Trials

Ongoing Trials on Selective progesterone receptor modulator at Clinical Trials.gov

Trial results on Selective progesterone receptor modulator

Clinical Trials on Selective progesterone receptor modulator at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Selective progesterone receptor modulator

NICE Guidance on Selective progesterone receptor modulator

NHS PRODIGY Guidance

FDA on Selective progesterone receptor modulator

CDC on Selective progesterone receptor modulator

Books

Books on Selective progesterone receptor modulator

News

Selective progesterone receptor modulator in the news

Be alerted to news on Selective progesterone receptor modulator

News trends on Selective progesterone receptor modulator

Commentary

Blogs on Selective progesterone receptor modulator

Definitions

Definitions of Selective progesterone receptor modulator

Patient Resources / Community

Patient resources on Selective progesterone receptor modulator

Discussion groups on Selective progesterone receptor modulator

Patient Handouts on Selective progesterone receptor modulator

Directions to Hospitals Treating Selective progesterone receptor modulator

Risk calculators and risk factors for Selective progesterone receptor modulator

Healthcare Provider Resources

Symptoms of Selective progesterone receptor modulator

Causes & Risk Factors for Selective progesterone receptor modulator

Diagnostic studies for Selective progesterone receptor modulator

Treatment of Selective progesterone receptor modulator

Continuing Medical Education (CME)

CME Programs on Selective progesterone receptor modulator

International

Selective progesterone receptor modulator en Espanol

Selective progesterone receptor modulator en Francais

Business

Selective progesterone receptor modulator in the Marketplace

Patents on Selective progesterone receptor modulator

Experimental / Informatics

List of terms related to Selective progesterone receptor modulator

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists (such as progesterone) and full antagonists (such as RU 486) is that their action differs in different tissues (agonist in some while antagonist in others). This mixed agonist/agonist profile of action leads to selective stimulation or inhibition progesterone-like action in different tissues and furthermore raises the possibility of dissociation of desirable therapeutic effects from undesirable side effects in synthetic progesterone receptor drug candidates.[1]

## Contents

* 1 Members
* 2 Uses
* 3 Mechanism of action
* 4 References
* 5 See also

## Members

[edit | edit source]

Members include:

* Asoprisnil (J867)
* CDB-4124 (Proellex™, Progenta™)

## Uses

[edit | edit source]

SPRMs are in limited use:

* Asoprisnil and CDB-4124 are both under investigation (2005) for the medical treatment of uterine leiomyoma.

## Mechanism of action

[edit | edit source]

Synthetic SPRMs differ in chemical structure from the endogenous hormone progesterone, but nevertheless bind to the same progesterone receptor. In humans, there is only one gene (PGR) that codes for the receptor, but two splice variants (PR-A and -B) arising from this single gene each with a somewhat different tissue distribution and intrinsic functional activity in response to ligand binding (agonist vs. antagonist). In addition, synthetic SPRMs may have some binding selectivity between the two isoforms, although this is unlikely as the ligand binding domains of the two isoforms are identical.

A more likely origin of the tissue selectivity of SPRMs is what conformational preference these ligands induce in the receptor. The ligand binding domain of the receptor is in equilibrium between two different conformations. The first is an agonist conformation which favors the binding of coactivator proteins which in turn favors upregulation of gene transcription. The second is an antagonistic conformation which in contrast favors the binding of corepressors and as a consequence down regulation of gene expression. Full agonists such as progesterone which display agonist properties in all tissues, strongly shift the conformational equilibrium in the agonist direction. Conversely full antagonists such as RU-486 strongly shift the equilibrium in the antagonist direction. Finally, the overall ratio of concentrations of coactivator to corepressor may differ in different cell types.

When SPRMs bind to the progesterone receptor, the equilibrium between the two conformational states is more closely balanced and hence more easily perturbed by differences in the cellular environment. In tissues where the concentration of coactivators is higher than corepressors, the excess coactivators drive the equilibrium in the agonist direction. Conversely in tissues where corepressor concentration is higher the equilibrium is driven in the antagonist direction.[2][3] Hence SPRMs display agonist activity in tissues where coactivators predominate and antagonist activity where corepressors are in excess.

## References

[edit | edit source]

1. ↑ Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W (2005). "Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis". Endocr Rev. 26 (3): 423–38. doi:10.1210/er.2005-0001. PMID 15857972.CS1 maint: Multiple names: authors list (link)
2. ↑ Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB (1997). "The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT". Mol Endocrinol. 11 (6): 693–705. doi:10.1210/me.11.6.693. PMID 9171233.CS1 maint: Multiple names: authors list (link)
3. ↑ Smith CL, O'Malley BW (2004). "Coregulator function: a key to understanding tissue specificity of selective receptor modulators". Endocr Rev. 25 (1): 45–71. doi:10.1210/er.2003-0023. PMID 14769827.

## See also

[edit | edit source]

Selective estrogen receptor modulator

Template:Sex hormones

Template:WikiDoc Sources