Oral contraceptives modify DNA methylation and monocyte-derived macrophage function

Biology of Sex Differences

Ilaria Campesi⁴  Manuela Sanna⁴  Angelo Zinellu³  Ciriaco Carru³  Laura Rubattu²  Pamela Bulzomi⁸  Giuseppe Seghieri⁷  Giancarlo Tonolo⁵  Mario Palermo¹  Giuseppe Rosano⁶  Maria Marino⁸  Flavia Franconi⁴ 

[1] Servizio di Diagnosi e Cura di Endocrinologia, Azienda Ospedaliero-Universitaria, Sassari, Italy

[2] Laboratory Department, SS Annunziata Hospital, Sassari, Italy

[3] Department of Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari, Sassari, Italy

[4] Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari, Sassari, Italy

[5] SC Diabetologia Aziendale ASL 2 Olbia, Hospital San Giovanni di Dio, Olbia, Italy

[6] IRCCS San Raffaele Pisana, Rome, Italy

[7] Department of Internal Medicine, Spedali Riuniti, Pistoia, Italy

[8] Department of Biology, University Roma Tre, Rome, Italy

关键词: TNFα;    monocyte-derived macrophages;    global DNA methylation;    estrogen receptors;    combined oral contraceptive;    androgenic and non-androgenic progestin;   

Others  :  793781
DOI  :  10.1186/2042-6410-3-4

 received in 2011-10-24, accepted in 2012-01-27,  发布年份 2012

【 摘 要 】

Background

Fertile women may be encouraged to use contraception during clinical trials to avoid potential drug effects on fetuses. However, hormonal contraception interferes with pharmacokinetics and pharmacodynamics and modifies internal milieus. Macrophages depend on the milieu to which they are exposed. Therefore, we assessed whether macrophage function would be affected by the use of combined oral contraceptives (OCs) and if this influence depended on the androgenic or non-androgenic properties of progestin.

Methods

Healthy adult women were enrolled and stratified into two groups: women who did not use OCs (Fs) and women treated with OCs (FOCs). FOCs were further stratified as a function of androgenic (FOCA⁺) and non-androgenic (FOCA^-) properties of progestins. Routine hematological, biochemical, inflammatory and endothelial dysfunction parameters were measured. Monocyte-derived macrophages (MDMs) were evaluated for the expression and activity of estrogen receptors and androgen receptors, and release of tumor necrosis factor α (TNFα) was measured from unstimulated and lipopolysaccharide-stimulated cells.

Results

As is already known, the use of OCs changed numerous parameters: the number of lymphocytes, iron levels, total iron-binding capacity of transferrin, triglycerides, high-density lipoprotein, total cholesterol, and C-reactive protein increased, while prothrombin time and alkaline phosphatase decreased. Hormonal levels also varied: cortisol was higher in FOCs, while luteinizing hormone, follicle-stimulating hormone, and testosterone were lower in FOCs. Asymmetric dimethylarginine, an index of endothelial function, was lower in FOC than in Fs, as were cysteine and bilirubin. The androgenic properties of progestins affected the activity of OCs: in particular, white blood cell count, hemoglobin, high-density lipoprotein and calcium were higher in FOCA^- than in FOCA⁺, whereas percentage oxygen saturation and γ-glutamyl transpeptidase were lower in FOCA^- than in FOCA⁺. Importantly, FOCs had a lower global DNA methylation, indicating that OC may have epigenetic effects on gene expression. OC did not modify the expression of androgen receptor but increased estrogen receptor α expression, more considerably in FOCA⁺, and decreased estrogen receptor β, more considerably in FOCA^-. Importantly, the activation state of estrogen receptor β in FOCs was decreased, while estrogen receptor α was not active in either Fs or FOCs. Unstimulated MDMs obtained from FOCs showed higher release of TNFα in comparison with Fs. After lipopolysaccharide stimulation, the release of TNFα was significantly higher in Fs than in FOCs.

Conclusions

OC use induced many changes in hematological and plasmatic markers, modifying hormonal levels, endothelial function, inflammation index and some redox state parameters, producing a perturbation of the internal milieu that impacted macrophagic function. In fact, different levels of estrogen receptor expression and release of TNFα were observed in macrophages derived from OC users. Some of the above activities were linked to the androgenic properties of progestin. Even though it is not known whether these effects are reversible, the results indicate that to avoid potential skewing of results only a single type of OC should be used during a single clinical trial.

【 授权许可】

   
2012 Campesi et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

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