Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells

J Clin Endocrinol Metab. 2004 Jan;89(1):324-34. doi: 10.1210/jc.2003-030498.

Abstract

The decidualization of endometrial stromal cells in the secretory phase of the menstrual cycle is an essential prerequisite for the implantation of a blastocyst. This profound differentiation process is accompanied by sustained elevated intracellular cAMP concentrations in vivo. Primary cell cultures of endometrial stromal cells decidualize by treatment with cAMP-elevating agents in vitro. Our previous findings indicated that the cAMP-degrading activities of phosphodiesterases (PDE) and signaling of the peptide hormone relaxin are coupled in human endometrial stromal cells. In the present study we have chosen a pharmacological approach to test whether relaxin binding and PDE inhibition cooperate to induce decidualization. Measurement of PDE activity and relaxin-stimulated cAMP accumulation in the presence of diverse PDE inhibitors identified PDE4 and PDE8 as the principal PDE isoforms involved in human endometrial stromal cells. The PDE4 inhibitor rolipram was most effective in elevating intracellular cAMP concentrations and synergizing with relaxin to achieve maximal in vitro decidualization, as determined by measurement of the expression of the decidual marker genes for prolactin and IGF-binding protein-1 and measurement of prolactin secretion. Gene expression for PDE4D and PDE4C was significantly up-regulated during in vitro decidualization. Treatment of cell cultures with the protein kinase A inhibitor H89 revealed a minor role for protein kinase A-mediated positive feedback control of PDE4 activity in human endometrial stromal cells, consistent with sustained elevated cAMP essential for decidualization in vitro. These findings introduce the new idea of clinically applying the combination of a specific PDE4 inhibitor with an effector such as relaxin, thereby offering an alternative nonsteroidal luteal phase support for the endometrium to encourage endometrial development and implantation in subfertile women undergoing assisted reproductive technology procedures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / genetics
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Adult
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Decidua / physiology*
  • Drug Synergism
  • Endometrium / physiology*
  • Enzyme Inhibitors / pharmacology*
  • Feedback, Physiological
  • Female
  • Gene Expression
  • Humans
  • Insulin-Like Growth Factor Binding Protein 1 / genetics
  • Isoenzymes / antagonists & inhibitors
  • Isoquinolines / pharmacology
  • Middle Aged
  • Prolactin / genetics
  • Prolactin / metabolism
  • RNA, Messenger / analysis
  • Relaxin / metabolism*
  • Relaxin / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rolipram / pharmacology
  • Signal Transduction*
  • Stromal Cells / physiology*
  • Sulfonamides*

Substances

  • Enzyme Inhibitors
  • Insulin-Like Growth Factor Binding Protein 1
  • Isoenzymes
  • Isoquinolines
  • RNA, Messenger
  • Sulfonamides
  • Prolactin
  • Relaxin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4C protein, human
  • PDE4D protein, human
  • Rolipram
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide