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Comparative Study
. 2007 Dec;197(6):599.e1-7.
doi: 10.1016/j.ajog.2007.05.024.

Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins

Barbara J Attardi  1 , Anthony Zeleznik, Hyagriv Simhan, Jye Ping Chiao, Donald R Mattison, Steve N Caritis; Obstetric-Fetal Pharmacology Research Unit Network
Affiliations
Comparative Study

Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins

Barbara J Attardi et al. Am J Obstet Gynecol. 2007 Dec.

Abstract

Objective: This study was undertaken to determine whether the reduction in premature birth attributable to 17-alpha hydroxyprogesterone caproate occurs because of a greater affinity for progesterone or glucocorticoid receptors or by enhanced stimulation of progestogen responsive genes when compared with progesterone.

Study design: We performed competitive steroid hormone receptor binding assays using cytosols expressing either recombinant human progesterone receptor-A or -B or rabbit uterine or thymic cytosols. We used 4 different carcinoma cell lines to assess transactivation of reporter genes or induction of alkaline phosphatase.

Results: Relative binding affinity of 17-alpha hydroxyprogesterone caproate for recombinant human progesterone receptor-B, recombinant human progesterone receptor-A, and rabbit progesterone receptors was 26-30% that of progesterone. Binding of progesterone to rabbit thymic glucocorticoid receptors was weak. 17-alpha hydroxyprogesterone caproate was comparable to progesterone in eliciting gene expression in all cell lines studied.

Conclusion: Binding to progesterone receptors, glucocorticoid receptors, or expression of progesterone-responsive genes is no greater with 17-alpha hydroxyprogesterone caproate than with progesterone. Other mechanisms must account for the beneficial effect of 17-alpha hydroxyprogesterone caproate on preterm birth rates.

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Figures

Fig. 1
Fig. 1
Chloramphenicol acetyltransferance (CAT) concentrations in T47D-2963.1 cells after incubation with various progestins. Four experiments were performed in duplicate with 100,000 cells/well (see Materials & Methods section). Values represent means ± SEM.
Fig. 2
Fig. 2
Luminescence units after incubation of 50,000 cells for 48 hours with various progestins. Four experiments were performed in duplicate. (See Materials & Methods section). Values represent means ± SEM.
Fig. 3
Fig. 3
Inhibition of 17-OHPC-stimulated transcription or alkaline phosphatase activity in T47Dco cells by the antiprogestins, mifepristone or CDB-4124. T47Dco cells were treated with vehicle, 10−8 M 17-OHPC, or 17-OHPC in the presence of various concentrations of A, C. mifepristone or B,D. CDB-4124 (10−11 to 10−5 M). After 20 hours (A,B) or 72 hours (C,D), cells were washed and lysed for measurement of luciferase or alkaline phosphatase activity, respectively, as specified in Materials and Methods. The data represent the mean ± SD of duplicate (transcription) or quadruplicate (alkaline phosphatase) values. Experiments were repeated 2–3 times.
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References

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