Research
Oral contraceptives modify DNA methylation and monocyte-derived macrophage function
Biology of Sex Differences 2012, 3:4 doi:10.1186/2042-6410-3-4
Published: 27 January 2012Abstract (provisional)
Background
Fertile women may be encouraged to use contraception during clinical trial to avoid drug effects on foetuses. 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 haematological, biochemical, inflammatory and endothelial dysfunction parameters were measured. Monocyte-derived macrophages (MDMs) were evaluated for the expression and activity of oestrogen receptors and androgen receptors, and release of tumour necrosis factor-alpha (TNF-alpha) was measured from unstimulated and lipopolysaccharide-stimulated cells.
Results
As 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 asset also varied: cortisol was higher in FOCs, while luteinising 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, haemoglobin, high-density lipoprotein and calcium were higher in FOCA- than in FOCA+, whereas % oxygen saturation and gamma-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 oestrogen receptor-alpha expression, more considerably in FOCA+, and decreased oestrogen receptor-beta, more considerably in FOCA-. Importantly, the activation state of oestrogen receptor-beta in FOCs was decreased, while oestrogen receptor-alpha was not active in either Fs or FOCs. Unstimulated MDMs obtained from FOCs showed higher release of TNF-alpha in comparison with Fs. After lipopolysaccharide stimulation, the release of TNF-alpha was significantly higher in Fs than in FOCs.
Conclusions
OC use induced many changes in haematological and plasmatic markers, modifying hormonal asset, endothelial function, inflammation index and some parameters of redox state, producing a perturbation of the internal milieu that impacted macrophagic function. In fact, different levels of oestrogen receptor expression and release of TNF-alpha 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 a single type of OC should be used during a single clinical trial.