The structures of membrane receptors mediating rapid, nongenomic actions of steroids have not been identified. We describe the cloning of a cDNA from spotted seatrout ovaries encoding a protein that satisfies the following seven criteria for its designation as a steroid membrane receptor: plausible structure, tissue specificity, cellular distribution, steroid binding, signal transduction, hormonal regulation, and biological relevance. For plausible structure, computer modeling predicts that the protein has seven transmembrane domains, typical of G protein-coupled receptors. The mRNA (4.0 kb) is only detected in the brain and reproductive tissues on Northern blots. Antisera only detect the protein (40 kDa) in plasma membranes of reproductive tissues. The recombinant protein produced in an Escherichia coli expression system has a high affinity (Kd = 30 nM), saturable, displaceable, single binding site specific for progestins. Progestins alter signal transduction pathways, activating mitogen-activated protein kinase and inhibiting adenylyl cyclase, in a transfected mammalian cell line. Inhibition of adenylyl cyclase is pertussis toxin sensitive, suggesting the receptor may be coupled to an inhibitory G protein. Progestins and gonadotropin up-regulate both mRNA and protein levels in seatrout ovaries. Changes in receptor abundance in response to hormones and at various stages of oocyte development, its probable coupling to an inhibitory G protein and inhibition of progestin induction of oocyte maturation upon microinjection of antisense oligonucleotides are consistent with the identity of the receptor as an intermediary in oocyte maturation. These characteristics suggest the fish protein is a membrane progestin receptor mediating a “nonclassical” action of progestins to induce oocyte maturation in fish.

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Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes

Computer assisted semen analyzers in andrology research and veterinary practice

Losel, Ralf M., Elisabeth Falkenstein, Martin Feuring, Armin Schultz, Hanns-Christian Tillmann, Karin Rossol-Haseroth, and Martin Wehling. Nongenomic Steroid Action: Controversies, Questions, and A...

Nongenomic Steroid Action: Controversies, Questions, and Answers

RU486 (mifepristone) has proved to be a remarkably active antiprogesterone and antiglucocorticosteroid agent in human beings. The mechanism of action involves the intracellular receptors of the antagonized hormones (progesterone and glucocorticosteroids). At the molecular level, the most important features are high binding affinity to the receptor, interaction of the phenylaminodimethyl group in the 11β-position with a specific region of the receptor binding pocket, and RU486-induced transconformation differences in the ligand-binding domain. These particularities have consequences at different steps of the receptor function as compared with agonists. However, the reasoning cannot be limited to the RU486-receptor interaction, and, for instance, there is the possibility of a switch from antagonistic property to agonist activity, depending on the intervention of other signaling pathways. It would be desirable to have derivatives with only one of the two antagonistic properties (antiprogestin, antiglucocorticosteroid) in spite of similarities between steroid structures, receptors involved, and responsive machineries in target cells. Clinically, the RU486-plus-prostaglandin method is ready to be used on a large scale and is close to being as convenient and safe as any medical method of abortion may be. The early use of RU486 as a contragestive as soon as a woman fears a pregnancy she does not want will help to defuse the abortion issue. Research should now be conducted to define an efficient and convenient contraceptive method with RU486 or other antiprogestins. The usefulness of RU486 for obstetric indications, including facilitation of difficult delivery, has to be assessed rapidly. Gynecologic trials, particularly

http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Medicine/Mifepristone.pdf

RU486 (MIFEPRISTONE): Mechanisms of Action and Clinical Uses

The identification of human sperm hyperactivated motility has potential importance in sperm function tests, as well as in quality control assays and in reproductive toxicology investigations. However, relatively little is known about this phenomenon and the variety of definitions used for hyperactivation has led to a great deal of confusion as to its occurrence and physiological relevance. This presentation is a critical review of a number of aspects of hyperactivated motility, including its identification and potential role(s) in mammalian fertilization. The initial sections of the review consider the mechanisms involved in the development and maintenance of mammalian sperm motility, and the structural and functional changes in spermatozoa which occur during transport through the female reproductive tract. The methods available for the quantification of aspects of sperm movement are also discussed, with an historical overview of sperm movement analysis.

/pdf/a-critical-review-of-the-physiological-importance-and-24713rvrib.pdf

A critical review of the physiological importance and analysis of sperm movement in mammals

Progesterone induced a rapid influx of calcium in capacitated human sperm, followed by a long-lasting, dose-dependent increase of intracellular free calcium. Thereafter, progesterone increased the fraction of hyperactivated sperm and the acrosome reaction. On the contrary, the progesterone antagonist RU486 (mifepristone) induced an immediate and transient, dose-dependent decrease of intracellular free calcium and a drop in the values of sperm movement parameters related to hyperactivation. Moreover, RU486 counteracted the effects of progesterone on calcium influx, lateral sperm head displacement, and the acrosome reaction. Therefore, RU486 effects were opposite to those of progesterone. The nature of the membrane receptor(s) involved is unknown. Several steroids bearing 11 beta-phenyl substitutions, with different pharmacological profiles, were also investigated. It was concluded that the steroid structure and chemical groups added to the 11 beta-phenyl influence effects on calcium influx.

https://www.jstor.org/stable/info/2363917

Catherine Serres

Papers

Progesterone and RU486: opposing effects on human sperm.

Sliding spermatozoa: a dyskinesia responsible for human infertility?