The Journal of Membrane Biology

, Volume 248, Issue 4, pp 811–824 | Cite as

Effect of Progesterone, Its Hydroxylated and Methylated Derivatives, and Dydrogesterone on Lipid Bilayer Membranes

  • Rola Abboud
  • Hélène Greige-Gerges
  • Catherine Charcosset


The interaction of progesterone (PG), 17-hydroxyprogesterone (17-OHPG), 21-hydroxyprogesterone (21-OHPG), medroxyprogesterone (MP), medroxyprogesterone acetate (MPA), and dydrogesterone (DYG), with zwitterionic dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposome, was investigated as a function of drug concentration using Fourier transform infrared spectroscopy and differential scanning calorimetry. The results reveal that progesterone and its derivatives changed the physical properties of the DPPC bilayers by decreasing the main phase-transition temperature (T m) and enthalpy (ΔH m), abolishing the pre-transition and disordering the membrane. From the thermodynamic parameters analysis, we concluded that PG, 21-OHPG, and MPA are localized inside the membrane. Whereas, the insertion of 17-OHPG in the lipid bilayers cannot be excluded in view of the significant decrease in the transition enthalpy at two molar ratios. MP and DYG are rather localized near the polar heads of phospholipids at the interface water-lipid bilayer. PG derivatives increase the membrane fluidity in the order: PG ≈ 21-OHPG ≈ MPA > 17-OHPG > MP ≈ DYG. The distinct effects produced by steroids are discussed in terms of hydrophobicity and chemical structure.


Dydrogesterone Hydroxyprogesterone Liposome Medroxyprogesterone Medroxyproegesterone acetate Progesterone 



Authors thank the Doctoral School of Sciences and Technologies at the Lebanese University for supporting the Bioactive Molecules Research Group.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Al-Asmakh M (2007) Reproductive functions of progesterone. Middle East Fertil Soc J 12(3):147–152Google Scholar
  2. Alvarez Nunez FA, Yalkowsky SH (1997) Correlation between log P and ClogP for some steroids. J Pharm Sci 86(10):1187–1189CrossRefPubMedGoogle Scholar
  3. Bangham AD, Standish MM, Watkins JC (1965) Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 13:238–252CrossRefPubMedGoogle Scholar
  4. Bhardwaj U, Burgess DJ (2010) Physicochemical properties of extruded and non-extruded liposomes containing the hydrophobic drug dexamethasone. Int J Pharm 388:181–189CrossRefPubMedGoogle Scholar
  5. Biruss B, Dietl R, Valenta C (2007) The influence of selected steroid hormones on the physicochemical behavior of DPPC liposomes. Chem Phys Lipids 148:84–90CrossRefPubMedGoogle Scholar
  6. Boyar H, Severcan F (1997) Oestrogen-phospholipid membrane interactions: an FTIR study. J Mol Struct 408(409):269–272CrossRefGoogle Scholar
  7. Carlson JC, Gruber MY, Thompson JE (1983) A Study of the interaction between progesterone and membrane lipids. Endocrinology 113:190CrossRefPubMedGoogle Scholar
  8. Colombo D, Ferraboschi P, Prestileo P, Toma L (2006) A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy. J Steroid Biochem Mol Biol 98:56–62CrossRefPubMedGoogle Scholar
  9. Cong W, Liu Q, Liang Q, Wang Y, Luo G (2009) Investigation of the interactions between pirarubicin and phospholipids. Biophys Chem 143:154–160CrossRefPubMedGoogle Scholar
  10. De Ziegler DF (2000) Progesterone and progestins: applications in gynecology. Steroids 65:671–679CrossRefPubMedGoogle Scholar
  11. Dicko A, Morissette M, Ben Ameur S, Pézolet M, Di Paolo T (1999) Effect of estradiol and tamoxifen on brain membranes: investigation by infrared and fluorescence spectroscopy. Brain Res Bull 49:401–405CrossRefPubMedGoogle Scholar
  12. Dunn JF, Nisula BC, Rodbard D (1981) Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 53:58–68CrossRefPubMedGoogle Scholar
  13. Ehring GR, Kerschbaum HH, Eder C, Neben AL, Fanger CM, Khoury RM et al (1998) A nongenomic mechanism of progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes. J Exp Med 188(9):1593–1602PubMedCentralCrossRefPubMedGoogle Scholar
  14. El Maghraby GM, Williams AC, Barry BW (2005) Drug interaction and location in liposomes: correlation with polar surface areas. Int J Pharm 292:179–185CrossRefPubMedGoogle Scholar
  15. Elhissi AM, O’Neill MA, Roberts SA, Taylor KM (2006) A calorimetric study of dimyristoylphosphatidylcholine phase transitions and steroid–liposome interactions for liposomes prepared by thin film and proliposome methods. Int J Pharm 320:124–130CrossRefPubMedGoogle Scholar
  16. Gallay J, De Kruijff B (1984) Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine. Eur J Biochem 142:105–112CrossRefPubMedGoogle Scholar
  17. Habib L, Khreich N, Jraij A, Abbas S, Magdalou J, Charcosset C et al (2013) Preparation and characterization of liposomes incorporating cucurbitacin E, a natural cytotoxic triterpene. Int J Pharm 13:238–252Google Scholar
  18. Heimburg T (2000) A model for the lipid pretransition: coupling of ripple formation with the chain-melting transition. Biophys J 78:1154–1165PubMedCentralCrossRefPubMedGoogle Scholar
  19. Iswari S, Colas AE, Karavolas HJ (1986) Binding of 5 alpha dihydroprogesterone and other progestin to female rat anterior pituitary nuclear extracts. Steroids 47(2–3):189–203CrossRefPubMedGoogle Scholar
  20. Jain MK, Wu NM (1977) Effect of small molecules on the dipalmitoyl lecithin liposomal bilayer: phase transition in lipid bilayer. J Membr Biol 34:157–201CrossRefGoogle Scholar
  21. Kazanci N, Toyran N, Haris P, Severcan F (2001) Vitamin D2 at high and low concentrations exert opposing effects on molecular order and dynamics of dipalmitoyl phosphatidylcholine membranes. Spectroscopy 15:47–55CrossRefGoogle Scholar
  22. Korkmaz F, Severcan F (2005) Effect of progesterone on DPPC membrane: evidence for lateral phase separation and inverse action in lipid dynamics. Arch Biochem Biophys 440:141–147CrossRefPubMedGoogle Scholar
  23. Korkmaz F, Kırbıyık H, Severcan F (2005) Concentration dependent different action of progesterone on the order, dynamics and hydration states of the head group of dipalmitoyl-phosphatidylcholine membrane. Spectroscopy 19:213–219CrossRefGoogle Scholar
  24. Lewis R, McElhaney R (1998) The structure and organization of phospholipid bilayers as revealed by infrared spectroscopy. Chem Phys Lipids 96:9–21CrossRefGoogle Scholar
  25. Liang Y, Belford S, Tang F, Prokai L, Simpkins J, Hughes J (2001) Membrane fluidity effects of estratrienes. Brain Res Bull 54:661–668CrossRefPubMedGoogle Scholar
  26. McEwen BS (1994) Steroid hormone actions on the brain: when is the genome involved? Horm Behav 28(4):396–405CrossRefPubMedGoogle Scholar
  27. Mendoza C, Soler A, Tesarik J (1996) Nongenomic steroid action: independent targeting of a plasma membrane calcium channel and a tyrosine kinase. Biochem Biophys Res Commun 210(2):518–523CrossRefGoogle Scholar
  28. Olive DL (2002) Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv 57:55–63CrossRefGoogle Scholar
  29. Prades J, Vogler O, Alemany R, Gomez-Florit M, Funari S, Ruiz-Gutierrez V et al (2011) Plant pentacyclic triterpenic acids as modulators of lipid membrane physical properties. Biochim Biophys Acta 1808:752–760CrossRefPubMedGoogle Scholar
  30. Sanchez-Bueno AW (1991) Studies of conformation and interaction of the cyclohexenone and acetyl group of progesterone with liposomes. J Steroid Biochem Mol Biol 38:171–179CrossRefGoogle Scholar
  31. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW et al (2003) Classification and pharmacology of progestins. Maturitas 46:7–16CrossRefGoogle Scholar
  32. Skiba ML, Barbot C, Bounoure F, Joudieh S, Skiba M (2006) Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems. Drug Dev Ind Pharm 32:1043–1058CrossRefPubMedGoogle Scholar
  33. Soderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit H (2004) Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology 29:339–354CrossRefPubMedGoogle Scholar
  34. Sun Y, Cai J, Ma F, Lu P, Huang H, Zhou J (2012) miR-155 mediates suppressive effect of progesterone on TLR3, TLR4-triggered immune response. Immunol Lett 146:25–30CrossRefPubMedGoogle Scholar
  35. Torres-Cartas S, Villanucva-Carmanãs R, Garcia-Alvarez-Coque M (2000) Retention-structure relationship studies for some steroidal hormones in micellar liquid chromatography. Chromatographia 51(9–10):577–585CrossRefGoogle Scholar
  36. Tsuda K, Kinoshita Y, Nishio I (2002) Synergistic role of progesterone and nitric oxide in the regulation of membrane fluidity of erythrocytes in humans: an electron paramagnetic resonance investigation. Am J Hypertens 15(8):702–708CrossRefPubMedGoogle Scholar
  37. Vijayan R, Biggin PC (2008) A steroid in a lipid bilayer: localization, orientation, and energetics. Biophys J 95:45–47CrossRefGoogle Scholar
  38. Wenz JJ (2012) Predicting the effect of steroids on membrane biophysical properties based on the molecular structure. Biochim Biophys Acta 1818:896–906CrossRefPubMedGoogle Scholar
  39. Whiting KP, Restall CJ, Brain PF (2000) Steroid hormone-induced effects on membrane fluidity and their potential roles in non-genomic mechanisms. Life Sci 67:743–757CrossRefPubMedGoogle Scholar
  40. Wood EJ (2006) Marks’ basic medical biochemistry: a clinical approach (second edition). Biochem Mol Biol Educ 34:395CrossRefPubMedGoogle Scholar
  41. Zhang Y, Wang Z, Ma Z, Cheng Y (2008) Characterization of progesterone derivatives by LC-DAD-ESI/MSn and its application to the identification of impurities in flurogestone acetate. Chromatographia 68:903–909CrossRefGoogle Scholar
  42. Zhao X, Liu L, Liu D, Fan H, Wang Y, Hu Y et al (2012) Progesterone enhances immunoregulatory activity of human mesenchymal stem cells via PGE2 and IL-6. Am J Reprod Immunol 68:290–300CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Rola Abboud
    • 1
    • 2
  • Hélène Greige-Gerges
    • 1
  • Catherine Charcosset
    • 2
  1. 1.Bioactive Molecules Research Group, PRASE, Doctoral School of Sciences and Technologies, Department of Chemistry and Biochemistry, Faculty of Sciences 2Lebanese UniversityBeirutLebanon
  2. 2.Laboratoire d’Automatique et de Génie des Procédés (LAGEP), UMR-CNRS 5007Université Claude Bernard Lyon 1Villeurbanne CedexFrance

Personalised recommendations