ABSTRACT
Title
Combined oral contraceptives induce epigenetic modifications and change in expression and activity of estrogen receptors in monocyte-derived macrophages
Authors
I. Campesi1,2,3, M. Sanna1,2,3, A. Zinellu4,5 C. Carru2,4, L. Rubattu6, P. Bulzomi7, G. Seghieri8, G. Tonolo9, M. Palermo10, G. Rosano11, M. Marino7 and F. Franconi1,2,3
1 Department of Pharmacology, University of Sassari,
2 National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy
3 Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
4 Dept. Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
5 Porto Conte Ricerche Srl, Tramariglio, Alghero, Sassari, Italy
6 Laboratory Department., SS Annunziata Hospital, Sassari 3 Department Biomedical Sciences, University of Sassari
7 Department of Biology, University Roma Tre V.le G. Marconi, 446 00146 Rome. Italy
8 Department of Internal Medicine, Spedali Riuniti, Pistoia, Italy
9 SC Diabetologia Aziendale ASL 2 Olbia, Hospital San Giovanni di Dio, via A Moro, Olbia, Italy
10 Institute of Endocrinology, AOU, Sassari.
11 IRCCS San Raffaele Pisana, Rome, Italy
1 Department of Pharmacology, University of Sassari,
2 National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy
3 Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
4 Dept. Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
5 Porto Conte Ricerche Srl, Tramariglio, Alghero, Sassari, Italy
6 Laboratory Department., SS Annunziata Hospital, Sassari 3 Department Biomedical Sciences, University of Sassari
7 Department of Biology, University Roma Tre V.le G. Marconi, 446 00146 Rome. Italy
8 Department of Internal Medicine, Spedali Riuniti, Pistoia, Italy
9 SC Diabetologia Aziendale ASL 2 Olbia, Hospital San Giovanni di Dio, via A Moro, Olbia, Italy
10 Institute of Endocrinology, AOU, Sassari.
11 IRCCS San Raffaele Pisana, Rome, Italy
Abstract
The U.S. Food and Drug Administration (FDA) encourages the enrolment of women in clinical trials which test the efficacy and safety of pharmacological therapy. The protocol designs emphasize the need for contraception for women of childbearing potential who participate in early drug trials. Certain aspects of contraceptive requirements for such studies do not appear to have been sufficiently considered, including the fact that hormonal contraception may interfere with pharmacokinetics or even pharmacodynamics. In this study we focused our attention on monocyte-derived macrophages (MDMs) which play a lead role in atherosclerosisand immunity, are influenced by the milieu to which they are exposed and contain estrogen (ER) and androgen receptors (AR). We selected combined oral contraceptives (OCs), which are the most commonly used birth control methods all over the world. Specifically we selected OCs containing the same estrogen and androgenic or non-androgenic progestin to analyze and compare plasma hematological and biochemical parameters and expression and the activity of ER and AR together with a typical macrophage function such as tumor necrosis factor-α (TNF-α) release.
Here we evidenced that combined oral contraceptives with (FOCA+) or without androgenic progestin (FOCA-)influenced many plasma parameters including hemoglobin, white blood cells count, calcium, high density lipoprotein and thyroid-stimulating hormone that resulted higher in FOCA- than in FOCA+. Conversely, % saturation and gamma-glutamyl transpeptidasewere lower in FOCA- than in FOCA+. Global DNA-methylation, endothelial dysfunction parameters and homocysteine were lower in both FOCA- and FOCA+ than in non-users of OCs.
At cellular level tumor necrosis factor αlpha from unstimulated MDMs was higher in FOCA+ than in FOCA-, whereas after lipopolysaccharide (LPS) stimulation the release was higher in FOCA- than in FOCA+. Estrogen receptor levels and activation status were also differently influenced by contraceptives in MDMs.
The findings suggest that contraceptive therapy impacts on many physical processes inducing divergent variations, which can depend on their formulation, and this could impact on pharmacological responses. Thus it is advisable to recommend the use of a single contraceptive in each clinical trial in order to improve help drug therapy in women.
Here we evidenced that combined oral contraceptives with (FOCA+) or without androgenic progestin (FOCA-)influenced many plasma parameters including hemoglobin, white blood cells count, calcium, high density lipoprotein and thyroid-stimulating hormone that resulted higher in FOCA- than in FOCA+. Conversely, % saturation and gamma-glutamyl transpeptidasewere lower in FOCA- than in FOCA+. Global DNA-methylation, endothelial dysfunction parameters and homocysteine were lower in both FOCA- and FOCA+ than in non-users of OCs.
At cellular level tumor necrosis factor αlpha from unstimulated MDMs was higher in FOCA+ than in FOCA-, whereas after lipopolysaccharide (LPS) stimulation the release was higher in FOCA- than in FOCA+. Estrogen receptor levels and activation status were also differently influenced by contraceptives in MDMs.
The findings suggest that contraceptive therapy impacts on many physical processes inducing divergent variations, which can depend on their formulation, and this could impact on pharmacological responses. Thus it is advisable to recommend the use of a single contraceptive in each clinical trial in order to improve help drug therapy in women.