Unusual steroid specificity of the cell surface progesterone receptor on human sperm.
The steroid specificity of the cell surface progesterone receptor in human sperm was examined with the use of progesterone, testosterone, and androstane analogues. Many compounds were shown to be more effective than progesterone at increasing intracellular free calcium concentration, e.g., 2 alpha-methyl-17beta-methoxy-5 alpha-androstan-3-one. Several testosterone analogues were demonstrated to be antagonists of progesterone, e.g., 9(11)-dehydro-2 alpha,17alpha-dimethyltestosterone. The synthetic potent progestigens, norethynodrel, cyproterone acetate, norethindrone, and megestrol acetate, were found to be only weak stimulators of the sperm cell surface receptor. Furthermore, these compounds were shown to antagonize the effect of progesterone to elevate intracellular free calcium concentration in sperm. It is known that progesterone and some of its analogues bind to the intracellular progesterone nuclear receptor via the alpha-face of the steroid molecule. In stark contrast, it was concluded from the analysis of the steroid analogues examined on human sperm in this study that intimate contact exists between the effective progesterone analogues and the sperm cell surface progesterone receptor across the beta-face of the steroid C/D-ring "upper" edge (C11, C12, and C17). Positioning of the C21 methyl group is also critical for efficacy, and recognition of the steroid A-ring seems not to be involved.
Blackmore
P F
PF
Department of Pharmacology, Eastern Virginia Medical School, Norfolk 23501, USA.
Fisher
J F
JF
Spilman
C H
CH
Bleasdale
J E
JE
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects*; D013329:Structure-Activity Relationship
D011980:Receptors, Progesterone; D011374:Progesterone