A Study of the Role of Membrane Progesterone Receptors During Pregnancy and Labor in Rats

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Abstract

Progesterone plays a major role in preparing the female body for and maintaining pregnancy. Classical nuclear progesterone receptors (nPRs) have been found in the female reproductive organs, through interaction with which progesterone exerts multiple effects in these tissues. Recently, membrane progesterone receptors (mPRs) have also been found in the uterus, placenta, ovaries, and mammary glands of humans and animals. It is assumed that these receptors fulfil important functions in the maintenance of pregnancy, in the initiation of labour. However, their role in these processes has not been studied. Earlier in our work, we identified two compounds that have affinity for mPRs of different subtypes but do not interact with nPRs. Their actions have been demonstrated in various cells but have not been studied in vivo. In this work, the main aim was to study the action of one of these steroids (LS-01) in a classical test for pregnancy maintenance in ovariectomised female rats and for stimulation of the labour process to identify the role of mPRs. To analyse the main targets of mPRs selective ligand action in utero, we examined the expression of all five mPRs subtypes as well as nPRs and the membrane component of the progesterone receptor (PGRMC1) before, during and after pregnancy termination. From this study, we did not detect an effect of LS-01 on either pregnancy maintenance or labour induction in rats. However, the study of progesterone receptor expression profile and correlations of this profile with serum sex steroid concentrations suggests a different role of membrane receptor subtypes: progesterone acting through mPRγ and nPRs may promote pregnancy maintenance, while acting through mPRβ may promote labour initiation. To identify the functions of different subtypes of mPRs in reproduction and the fine regulation of this process, the search for ligands selective for each membrane receptor is necessary.

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About the authors

M. A. Vodopetova

Lomonosov Moscow State University

Email: schelkunova-t@mail.ru
Russian Federation, Moscow

A. D. Dmitrieva

Lomonosov Moscow State University

Email: schelkunova-t@mail.ru
Russian Federation, Moscow

I. S. Levina

Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences

Email: schelkunova-t@mail.ru
Russian Federation, Moscow

I. A. Morozov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: schelkunova-t@mail.ru
Russian Federation, Moscow

P. M. Rubtsov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: schelkunova-t@mail.ru
Russian Federation, Moscow

O. V. Smirnova

Lomonosov Moscow State University

Email: schelkunova-t@mail.ru
Russian Federation, Moscow

T. A. Shchelkunova

Lomonosov Moscow State University

Author for correspondence.
Email: schelkunova-t@mail.ru
Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. LS-01: 19-hydroxypregn-3-en-20-one.

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3. Fig. 2. Changes in serum progesterone (left) and estradiol (right) concentrations in rats during estrus and pregnancy. Data are presented as median and interquartile range.

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4. Fig. 3. Changes in the mRNA level of mPRs, nPRs and PGRMC1 in the rat uterus during estrus and pregnancy. Data are presented as median and interquartile range.

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5. Fig. 4. (a) – Correlation between mPRγ and nPRs expression in the estrus phase and during pregnancy. (b) – Correlation between mPRβ and nPRs expression in the estrus phase and during pregnancy. Data are presented as mean values of mRNA levels in relative units per calibrator.

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6. Fig. 5. Correlation between serum progesterone levels and mPRγ (a) and mPRβ (b) expression in the uterus of rats in estrus and during pregnancy. Receptor expression data are presented as mean mRNA levels in relative units per calibrator.

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7. Fig. 6. Correlation between serum estradiol levels and mPRβ (a) and mPRδ (b) expression in the uterus of rats in estrus and during pregnancy. Receptor expression data are presented as mean mRNA levels in relative units per calibrator.

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8. Fig. 7. Expression profile of COX2 (a), CCND1 (b), HSD11B1 (c) genes in the uterus of rats in the estrus phase and during pregnancy. Data are presented as median and interquartile range.

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9. Fig. 8. Serum progesterone concentrations in ovariectomized females in the first (a) and second (b) experiments examining the effects of progesterone and LS-01 on pregnancy maintenance. Data are presented as median with interquartile range.

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10. Fig. 9. Day of delivery in the experiment on stimulation of the labor process in the group with the introduction of a selective ligand and in the control group. Data are presented as median with interquartile range.

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