Prostaglandin F2a Binding Sites in Human Corpora Lutea CH. V. RAO, LARRY P. GRIFFIN, AND FRED R. CARMAN, JR. Department of Obstetrics Louisville, Kentucky 40202
and Gynecology,
University
ABSTRACT. The specific binding of 3H-prostaglandin (PG) F 2 a to homogenates of human corpora lutea of the cycle and ectopic pregnancy was examined. Corpora lutea of ectopic pregnancy bound significantly (P PGF,a > PGE 2 > PGEx > PGBX > PGA^ Figure 3 shows the time and temperature dependence of 3 H-PGF 2 a binding. There was a slow but gradual increase in 3HPGF 2 a binding at 22 C, reaching a steady state level by 1 h of incubation. Further incubation up to 4 h had no discernible effect on steady state levels bound. At 38 C, however, the initial rate of binding was higher compared to 22 C but fell quite rapidly after 30 min of incubation. The fall in binding at 38 C may be due to degradation of binding sites similar to the observations made in bovine corpus luteum cell membranes (21). TABLE 2. Effect of various additions on 3H-PGF;>a binding to homogenate of human corpus luteum 3
Additions Trypsin Pronase Trypsinogen EDTA, 10 mM EDTA + Ca2+, 10 mM
H-PGF2« bound (% of control) 6.8 0.0 63.6 7.6 389.2
± 2.9 ± 2.2 ± 1.4 ± 13.4
Homogenate protein (3.2 mg) was incubated with 0.5 mg enzyme for 1 h at 22 C. The tubes were centrifuged (6,000 x g for 15 min) to remove supernate, and the pellets were washed. Aliquots of washed pellets (399 jug protein) were incubated with 3H-PGF2a. The homogenates for control tubes were treated as above but without enzymes. EDTA and Ca2+ were added at the beginning of incubation with 3H-PGF.2a. Control tubes contained an equivalent volume of buffer. The 3HPGF-ja binding in control tubes varied from 8.2 to 24.9 fmol/mg protein which was taken as 100%.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 08:56 For personal use only. No other uses without permission. . All rights reserved.
1035
BINDING SITES IN HUMAN CORPORA LUTEA 1
1
gioo k - ^
•
-~
•
^
u u. o
PGE,
\ O
PGB,
—
o
60
z o
x
as a
(9
r
^
mtthyl P6F2a
\ /\
t
^
a. • 20 -
^ ^ .
k \. \^
PGF.a y
PGE 2 s. / ^^•^
^ " ^ ^ ^ -«.
PGF 2 a
I0" 7 UNLABELED PC's 3
FlG. 2. The specificity of H-PGF2a binding to homogenates of corpora lutea of ectopic pregnancy. The control tubes contained no competing unlabeled PG and the amount of 3H-PGF;ja bound in these tubes, 15.8 fmol/mg protein, was taken as 100%.
Table 2 shows that pretreatment of homogenates with trypsin and pronase drastically reduced, whereas trypsinogen moderately reduced 3 H-PGF 2 a binding. The loss of binding following pretreatment with trypsinogen may be due to the presence of the active enzyme (trypsin) in this enzyme preparation. The addition of EDTA which can chelate Ca2+ in the incubation media also drastically reduced the binding. This effect of EDTA was not only reversed by the addition of Ca2+, but also the binding greatly increased over control levels. The above results suggest that PGF 2 a binding sites are protein in nature and require cations for binding.
paper on the specificity and properties of these PGF 2 a binding sites. The 3 H-PGF 2 a binding was biphasic. Sites of 10~8M Kd were found in all the corpora lutea. The available number of these sites in all three corpora lutea varied. The results on PG structure vs. relative affinity for binding to 3 H-PGF 2 a sites revealed that a 9a-hydroxy group in the presence of a 5,6-double bond
Discussion The presence of PGF 2 a binding sites in human corpora lutea has been reported earlier by Powell et al. (12). The data presented in this paper are in agreement with the findings of the above authors as to the presence of PGF 2 a binding sites in human corpora lutea and the apparent Kd for one of the binding sites (10~ 8 M). Additional data are also presented in this
1 ,z
2
3
4
DURATION OF INCUBATION, HRS.
FIG. 3. The effects of time and temperature on 3 H-PGF2a binding to homogenates of human corpora lutea of ectopic pregnancy. The 3H-PGF2a binding, 11.2 fmol/mg protein, after 1 h at 22 C was taken as 100%.
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1036
JCE & M • 1977 Vol 44 • No 6
RAO, GRIFFIN AND CARMAN
primarily determines the affinity for binding to PGF2a sites (compare PGF2a with PGFja). The presence of a keto instead of hydroxy group on carbon 9 drastically reduced binding affinity for PGF 2 a sites (see PGEi). However, the presence of a 5,6-double bond in addition to a 9 keto group considerably improved the binding affinity (see PGE2). The absence of an 11-hydroxy group and the presence of a 10,11 or 8,12-double bond resulted in a further reduction in binding affinity (see PGAl5 PGBj). 15(S)15-methylPGF 2 a, had - 4 5 % lower affinity than the parent molecule. Among PGs tested, the relative affinity of 15(S)15-methyl-PGF2a may be of interest for the following reason: while there is no consistent evidence that PGF 2 a induces luteolysis in humans, 15(S)15-methyl PGF 2 a has been shown to have a consistent luteolytic effect as evidenced by a drop in peripheral plasma progesterone and estradiol levels in 8 out of 8 patients (16). This finding cannot be explained in terms of binding affinity because 15(S)15-methyl PGF 2 a has a lower affinity than PGF 2 a (see Fig. 2). It is quite likely that this observation reflects the slow clearance of this analog from the circulation. The following properties of PGF 2 a binding sites in human corpora lutea of ectopic pregnancy: a) biphasic nature of binding, b) PG structure vs. relative affinity for binding to PGF 2 a sites, c) rapid decline in binding at 38 C after 30 min of incubation when compared to 22 C, d) cationic requirement for binding, and e) protein nature of binding sites are remarkably similar to those found in bovine corpora lutea (12, 21, 23). The physiological significance of the finding that human corpora lutea of ectopic pregnancy contain significantly higher numbers of binding sites than those of the cycle is not known at the present time. Although the clear evidence for a luteolytic role for PGF 2 a in humans is yet to come, the presence of PGF 2 a binding sites in human corpora lutea should raise this possibility. Furthermore, the remarkable similarity of
sites in humans with respect to specificity and affinity with bovine corpora lutea, where it is generally accepted to be luteolytic (6), further strengthens the above possibility. A variety of recent evidence suggesting that PGF 2 a may indeed have a luteolytic effect in human corpus luteum (13-17) is also consistent with the above possibility. References 1. Powell, W. S., S. Hammarstrom, and B. Samuelsson, Prostaglandin F2a receptor in ovine corpora lutea, EurJ Biochem 41: 103, 1974. 2. Rao, Ch.V., The presence of discrete receptors for prostaglandin FM in the cell membranes of bovine coipora lutea, Biochem Biophys Res Commun 64: 416, 1975. 3. Powell, W. S., S. Hammarstrom, and B. Samuelsson, Occurrence and properties of prostaglandin F ^ receptor in bovine corpora lutea, Eur J Biochem 56: 73, 1975. 4. Kimball, F., and J. W. Lauderdale, Prostaglandin Ei and F ^ specific binding in bovine corpora lutea: Comparison with luteolytic potencies, Prostaglandin 10: 313, 1975. 5. Kimball, F., Prostaglandin F^a specific binding in equine corpora lutea, In Proceedings of Society for the Study of Reproduction, 1976, p. 37. 6. Hafs, H. D., T. M. Louis, P. A. Noden, and W. D. Oxender, Control of the estrous cycle with prostaglandin F ^ in cattle and horses,/ Anim Sci (Suppl 1) 38: 10, 1974. 7. Goding, J. R., The demonstration that PGFao: is the uterine luteolysin in the ewe, J Reprod Fertil 38: 261, 1974. 8. Roberts, J. S., B. Barcikowski, L. Wilson, R. C. Skarnes, and J. A. McCracken, Hormonal and related factors affecting the release of prostaglandin Fja from die uterus, J Steroid Biochem 6: 1091, 1975. 9. Scaramuzzi, R. J., and D. T. Baird, The oestrous cycle of the ewe after active immunization against prostaglandin Fja,,/ Reprod Fertil 46: 39, 1976. 10. Powell, W. S., S. Hammarstrom, B. Samuelsson, W. L. Miller, F. F. Sun, J. Fried, C. H. Lin, and J. Jarabak, Interaction between prostaglandin analogues and a receptor in bovine corpora lutea. Correlation of dissociation constants with luteolytic potencies in hamsters, Eur J Biochem 59: 271, 1975. 11. Rao, Ch. V., Discrete prostaglandin receptors in the outer cell membranes of bovine corpora lutea, In Samuelsson, B., and R. Paoletti (eds.), Advances in Prostaglandin and Thromboxane Research, vol. 1, Raven Press, New York, 1976, p. 247.
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PGF2a BINDING SITES IN HUMAN CORPORA LUTEA 12. Powell, W. S., S. Hammarstrom, B. Samuelsson, and B. Sjoberg, Prostaglandin F2a receptor in human corpora hi tea, Lancet 1: 1120, 1974. 13. Olcamura, H., T. Aso, Y. Yoshida, and T. Nishimura, Effects of prostaglandin F2a on human corpora lutea: An enzyme, histochemical, ultrastructural and hormonal study, Obstet Gynecol 44: 127, 1974. 14. McNatty, K. P., K. M. Henderson, and R. S. Sawers, Effects of prostaglandin F2a and E2 on tlie production of progesterone by human granulosa cells in tissue culture, J Endocrinol 67: 231, 1975. 15. Rao, B., and S. M. M. Karim, In vitro effects of IC1 81008, a PGFza analogue, on the human corpus luteum, IRCS Med Sci 3: 399, 1975. 16. Lauersen, N. H., and K. H. Wilson, Luteolytic and abortifacient effects of serial intramuscular injections of 15(S) 15-methyl prostaglandin F2a in early pregnancy, Am J Obstet Qynecol 126: 425, 1976. 17. Challis, J. R. C , A. A. Calder, S. Dilley, C. S. Forster, K. Hillier, D. J. S. Hunter, I. Z. MacKenzie, and G. D. Thorburn, Production of prostaglandin F ^ by corpora lutea, corpora albicantes and stroma from the human ovary, J Endocrinol 68: 401, 1976. 18. Lowry, O. H., N. J. Rosebrough, A. L. Farr, and R. J.
19. 20.
21. 22. 23.
24.
1037
Randall, Protein measurement with the Folin phenol reagent, / Biol Chem 193: 265, 1951. Rao, Ch.V., Characterization of prostaglandin receptors in bovine corpus luteum cell membranes, J Biol Chem 249: 7203, 1974. Grunnet, I., and E. Bojesen, Prostaglandin E, high affinity binding sites of rat thymocytes. Specificity and blockade by non-steroid antiinflammatory drugs and localization in a plasma membrane enriched fraction, Biochim Biophys Ada 419: 365, 1976. Rao, Ch. V., Properties of prostaglandin F2a receptors in bovine corpus luteum cell membranes, Mol Cell Endocrinol 6: 1, 1976. Scatchard, G., The attraction of proteins for small molecules and ions, Ann NY Acad Sci 15: 660,1949. Rao, Ch. V., Cationic dependency of high affinity prostaglandin F ^ receptors in bovine corpus luteum cell membranes, Biochem Biophys Res Commun 67: 1242, 1975. Rao, Ch.V., L. P. Griffin, and F. R. Carman, Jr., Binding sites for prostaglandin F ^ in homogenates of human corpus luteum, Endocrinology (Suppl) 98: 230, 1976 (Abstract).
National Conference on Clinical Trials Methodology Conference Date: Location:
October 3-4, 1977. Masur Auditorium, Clinical Center, Building 10, National Institutes of Health, Bethesda, Maryland. Proposed Program: October 3, 1977 Topics: Introduction: Importance of clinical trials and studies of clinical trials. Dr. Donald S. Fredrickson, Director, National Institutes of Health When and how should a clinical trial be stopped? Panel discussion. Chairman—Dr. Curtis Meinert, University of Maryland, School of Medicine Who will be effective as a clinical trials investigator and what are adequate incentives? Chairman—Dr. Robert Gordon, National Institutes of Health Patient recruitment: Problems and solutions. Chairman—Dr. Thaddeus Prout, Greater Baltimore Medical Center October 4, 1977 Topics: Quality Assurance of clinical data. Panel discussion. Co-chairmen—Dr. O. Dale Williams, University of North Carolina; Mr. Fred Ederer, National Institutes of Health Some ethnical problems of clinical trials. Chairman—Dr. Robert Levine, Yale University School of Medicine Possible activities to promote communication among investigators in clinical trials. Chairman—Dr. Harold P. Roth, National Institutes of Health No registration or notification of planned attendance is required. Additional information may be obtained by writing: Dr. Robert Gordon, Building 1, Room 107, National Institutes of Health, Bethesda, Maryland 20014.
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and Gynecology,
University
ABSTRACT. The specific binding of 3H-prostaglandin (PG) F 2 a to homogenates of human corpora lutea of the cycle and ectopic pregnancy was examined. Corpora lutea of ectopic pregnancy bound significantly (P PGF,a > PGE 2 > PGEx > PGBX > PGA^ Figure 3 shows the time and temperature dependence of 3 H-PGF 2 a binding. There was a slow but gradual increase in 3HPGF 2 a binding at 22 C, reaching a steady state level by 1 h of incubation. Further incubation up to 4 h had no discernible effect on steady state levels bound. At 38 C, however, the initial rate of binding was higher compared to 22 C but fell quite rapidly after 30 min of incubation. The fall in binding at 38 C may be due to degradation of binding sites similar to the observations made in bovine corpus luteum cell membranes (21). TABLE 2. Effect of various additions on 3H-PGF;>a binding to homogenate of human corpus luteum 3
Additions Trypsin Pronase Trypsinogen EDTA, 10 mM EDTA + Ca2+, 10 mM
H-PGF2« bound (% of control) 6.8 0.0 63.6 7.6 389.2
± 2.9 ± 2.2 ± 1.4 ± 13.4
Homogenate protein (3.2 mg) was incubated with 0.5 mg enzyme for 1 h at 22 C. The tubes were centrifuged (6,000 x g for 15 min) to remove supernate, and the pellets were washed. Aliquots of washed pellets (399 jug protein) were incubated with 3H-PGF2a. The homogenates for control tubes were treated as above but without enzymes. EDTA and Ca2+ were added at the beginning of incubation with 3H-PGF.2a. Control tubes contained an equivalent volume of buffer. The 3HPGF-ja binding in control tubes varied from 8.2 to 24.9 fmol/mg protein which was taken as 100%.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 08:56 For personal use only. No other uses without permission. . All rights reserved.
1035
BINDING SITES IN HUMAN CORPORA LUTEA 1
1
gioo k - ^
•
-~
•
^
u u. o
PGE,
\ O
PGB,
—
o
60
z o
x
as a
(9
r
^
mtthyl P6F2a
\ /\
t
^
a. • 20 -
^ ^ .
k \. \^
PGF.a y
PGE 2 s. / ^^•^
^ " ^ ^ ^ -«.
PGF 2 a
I0" 7 UNLABELED PC's 3
FlG. 2. The specificity of H-PGF2a binding to homogenates of corpora lutea of ectopic pregnancy. The control tubes contained no competing unlabeled PG and the amount of 3H-PGF;ja bound in these tubes, 15.8 fmol/mg protein, was taken as 100%.
Table 2 shows that pretreatment of homogenates with trypsin and pronase drastically reduced, whereas trypsinogen moderately reduced 3 H-PGF 2 a binding. The loss of binding following pretreatment with trypsinogen may be due to the presence of the active enzyme (trypsin) in this enzyme preparation. The addition of EDTA which can chelate Ca2+ in the incubation media also drastically reduced the binding. This effect of EDTA was not only reversed by the addition of Ca2+, but also the binding greatly increased over control levels. The above results suggest that PGF 2 a binding sites are protein in nature and require cations for binding.
paper on the specificity and properties of these PGF 2 a binding sites. The 3 H-PGF 2 a binding was biphasic. Sites of 10~8M Kd were found in all the corpora lutea. The available number of these sites in all three corpora lutea varied. The results on PG structure vs. relative affinity for binding to 3 H-PGF 2 a sites revealed that a 9a-hydroxy group in the presence of a 5,6-double bond
Discussion The presence of PGF 2 a binding sites in human corpora lutea has been reported earlier by Powell et al. (12). The data presented in this paper are in agreement with the findings of the above authors as to the presence of PGF 2 a binding sites in human corpora lutea and the apparent Kd for one of the binding sites (10~ 8 M). Additional data are also presented in this
1 ,z
2
3
4
DURATION OF INCUBATION, HRS.
FIG. 3. The effects of time and temperature on 3 H-PGF2a binding to homogenates of human corpora lutea of ectopic pregnancy. The 3H-PGF2a binding, 11.2 fmol/mg protein, after 1 h at 22 C was taken as 100%.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 08:56 For personal use only. No other uses without permission. . All rights reserved.
1036
JCE & M • 1977 Vol 44 • No 6
RAO, GRIFFIN AND CARMAN
primarily determines the affinity for binding to PGF2a sites (compare PGF2a with PGFja). The presence of a keto instead of hydroxy group on carbon 9 drastically reduced binding affinity for PGF 2 a sites (see PGEi). However, the presence of a 5,6-double bond in addition to a 9 keto group considerably improved the binding affinity (see PGE2). The absence of an 11-hydroxy group and the presence of a 10,11 or 8,12-double bond resulted in a further reduction in binding affinity (see PGAl5 PGBj). 15(S)15-methylPGF 2 a, had - 4 5 % lower affinity than the parent molecule. Among PGs tested, the relative affinity of 15(S)15-methyl-PGF2a may be of interest for the following reason: while there is no consistent evidence that PGF 2 a induces luteolysis in humans, 15(S)15-methyl PGF 2 a has been shown to have a consistent luteolytic effect as evidenced by a drop in peripheral plasma progesterone and estradiol levels in 8 out of 8 patients (16). This finding cannot be explained in terms of binding affinity because 15(S)15-methyl PGF 2 a has a lower affinity than PGF 2 a (see Fig. 2). It is quite likely that this observation reflects the slow clearance of this analog from the circulation. The following properties of PGF 2 a binding sites in human corpora lutea of ectopic pregnancy: a) biphasic nature of binding, b) PG structure vs. relative affinity for binding to PGF 2 a sites, c) rapid decline in binding at 38 C after 30 min of incubation when compared to 22 C, d) cationic requirement for binding, and e) protein nature of binding sites are remarkably similar to those found in bovine corpora lutea (12, 21, 23). The physiological significance of the finding that human corpora lutea of ectopic pregnancy contain significantly higher numbers of binding sites than those of the cycle is not known at the present time. Although the clear evidence for a luteolytic role for PGF 2 a in humans is yet to come, the presence of PGF 2 a binding sites in human corpora lutea should raise this possibility. Furthermore, the remarkable similarity of
sites in humans with respect to specificity and affinity with bovine corpora lutea, where it is generally accepted to be luteolytic (6), further strengthens the above possibility. A variety of recent evidence suggesting that PGF 2 a may indeed have a luteolytic effect in human corpus luteum (13-17) is also consistent with the above possibility. References 1. Powell, W. S., S. Hammarstrom, and B. Samuelsson, Prostaglandin F2a receptor in ovine corpora lutea, EurJ Biochem 41: 103, 1974. 2. Rao, Ch.V., The presence of discrete receptors for prostaglandin FM in the cell membranes of bovine coipora lutea, Biochem Biophys Res Commun 64: 416, 1975. 3. Powell, W. S., S. Hammarstrom, and B. Samuelsson, Occurrence and properties of prostaglandin F ^ receptor in bovine corpora lutea, Eur J Biochem 56: 73, 1975. 4. Kimball, F., and J. W. Lauderdale, Prostaglandin Ei and F ^ specific binding in bovine corpora lutea: Comparison with luteolytic potencies, Prostaglandin 10: 313, 1975. 5. Kimball, F., Prostaglandin F^a specific binding in equine corpora lutea, In Proceedings of Society for the Study of Reproduction, 1976, p. 37. 6. Hafs, H. D., T. M. Louis, P. A. Noden, and W. D. Oxender, Control of the estrous cycle with prostaglandin F ^ in cattle and horses,/ Anim Sci (Suppl 1) 38: 10, 1974. 7. Goding, J. R., The demonstration that PGFao: is the uterine luteolysin in the ewe, J Reprod Fertil 38: 261, 1974. 8. Roberts, J. S., B. Barcikowski, L. Wilson, R. C. Skarnes, and J. A. McCracken, Hormonal and related factors affecting the release of prostaglandin Fja from die uterus, J Steroid Biochem 6: 1091, 1975. 9. Scaramuzzi, R. J., and D. T. Baird, The oestrous cycle of the ewe after active immunization against prostaglandin Fja,,/ Reprod Fertil 46: 39, 1976. 10. Powell, W. S., S. Hammarstrom, B. Samuelsson, W. L. Miller, F. F. Sun, J. Fried, C. H. Lin, and J. Jarabak, Interaction between prostaglandin analogues and a receptor in bovine corpora lutea. Correlation of dissociation constants with luteolytic potencies in hamsters, Eur J Biochem 59: 271, 1975. 11. Rao, Ch. V., Discrete prostaglandin receptors in the outer cell membranes of bovine corpora lutea, In Samuelsson, B., and R. Paoletti (eds.), Advances in Prostaglandin and Thromboxane Research, vol. 1, Raven Press, New York, 1976, p. 247.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 08:56 For personal use only. No other uses without permission. . All rights reserved.
PGF2a BINDING SITES IN HUMAN CORPORA LUTEA 12. Powell, W. S., S. Hammarstrom, B. Samuelsson, and B. Sjoberg, Prostaglandin F2a receptor in human corpora hi tea, Lancet 1: 1120, 1974. 13. Olcamura, H., T. Aso, Y. Yoshida, and T. Nishimura, Effects of prostaglandin F2a on human corpora lutea: An enzyme, histochemical, ultrastructural and hormonal study, Obstet Gynecol 44: 127, 1974. 14. McNatty, K. P., K. M. Henderson, and R. S. Sawers, Effects of prostaglandin F2a and E2 on tlie production of progesterone by human granulosa cells in tissue culture, J Endocrinol 67: 231, 1975. 15. Rao, B., and S. M. M. Karim, In vitro effects of IC1 81008, a PGFza analogue, on the human corpus luteum, IRCS Med Sci 3: 399, 1975. 16. Lauersen, N. H., and K. H. Wilson, Luteolytic and abortifacient effects of serial intramuscular injections of 15(S) 15-methyl prostaglandin F2a in early pregnancy, Am J Obstet Qynecol 126: 425, 1976. 17. Challis, J. R. C , A. A. Calder, S. Dilley, C. S. Forster, K. Hillier, D. J. S. Hunter, I. Z. MacKenzie, and G. D. Thorburn, Production of prostaglandin F ^ by corpora lutea, corpora albicantes and stroma from the human ovary, J Endocrinol 68: 401, 1976. 18. Lowry, O. H., N. J. Rosebrough, A. L. Farr, and R. J.
19. 20.
21. 22. 23.
24.
1037
Randall, Protein measurement with the Folin phenol reagent, / Biol Chem 193: 265, 1951. Rao, Ch.V., Characterization of prostaglandin receptors in bovine corpus luteum cell membranes, J Biol Chem 249: 7203, 1974. Grunnet, I., and E. Bojesen, Prostaglandin E, high affinity binding sites of rat thymocytes. Specificity and blockade by non-steroid antiinflammatory drugs and localization in a plasma membrane enriched fraction, Biochim Biophys Ada 419: 365, 1976. Rao, Ch. V., Properties of prostaglandin F2a receptors in bovine corpus luteum cell membranes, Mol Cell Endocrinol 6: 1, 1976. Scatchard, G., The attraction of proteins for small molecules and ions, Ann NY Acad Sci 15: 660,1949. Rao, Ch. V., Cationic dependency of high affinity prostaglandin F ^ receptors in bovine corpus luteum cell membranes, Biochem Biophys Res Commun 67: 1242, 1975. Rao, Ch.V., L. P. Griffin, and F. R. Carman, Jr., Binding sites for prostaglandin F ^ in homogenates of human corpus luteum, Endocrinology (Suppl) 98: 230, 1976 (Abstract).
National Conference on Clinical Trials Methodology Conference Date: Location:
October 3-4, 1977. Masur Auditorium, Clinical Center, Building 10, National Institutes of Health, Bethesda, Maryland. Proposed Program: October 3, 1977 Topics: Introduction: Importance of clinical trials and studies of clinical trials. Dr. Donald S. Fredrickson, Director, National Institutes of Health When and how should a clinical trial be stopped? Panel discussion. Chairman—Dr. Curtis Meinert, University of Maryland, School of Medicine Who will be effective as a clinical trials investigator and what are adequate incentives? Chairman—Dr. Robert Gordon, National Institutes of Health Patient recruitment: Problems and solutions. Chairman—Dr. Thaddeus Prout, Greater Baltimore Medical Center October 4, 1977 Topics: Quality Assurance of clinical data. Panel discussion. Co-chairmen—Dr. O. Dale Williams, University of North Carolina; Mr. Fred Ederer, National Institutes of Health Some ethnical problems of clinical trials. Chairman—Dr. Robert Levine, Yale University School of Medicine Possible activities to promote communication among investigators in clinical trials. Chairman—Dr. Harold P. Roth, National Institutes of Health No registration or notification of planned attendance is required. Additional information may be obtained by writing: Dr. Robert Gordon, Building 1, Room 107, National Institutes of Health, Bethesda, Maryland 20014.
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