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Pregnancy is an immunological paradox that implies that a semi-allogeneic fetus is not rejected by the maternal immune system, from implantation of the embryo to delivery. Progesterone (P4), estradiol (E2) and human chorionic gonadotropin (hCG), contribute to the transformation of immune cells in a transient tolerance state, necessary to the maintenance of pregnancy. The effects of pregnancy hormones depend probably of their maternal plasma level. hCG is dangerous at high concentrations because it can stimulate autoantibodies production, whereas in physiological concentrations, hCG, P4 and E2 upregulate immune response expanding regulatory T and B cells, allowing the fetus to grow within the maternal uterus in a protective environment. A second example of fetal-maternal relation found recently is the role of maternal nutrition on development of the fetal hypothalamic neurons. Experiments in mice fed on a high fat diet reveal a critical timing when altered maternal metabolism affect formation of hypothalamic neurocircuits of the offspring and predispose him to long-term metabolic disorders., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Most combined oral contraceptive pills contain ethinyl estradiol (EE) with progestins. In order to minimize the pill's cardiovascular risks, the concept of using 17β-estradiol (E2), the endogenous estradiol, arose in the 1970s. Many attempts to develop a pill containing 17β-E2 have failed as cycle control was low. The first pill containing 17β-E2 was launched in 2011. This monophasic pill contains 24 pills with 1.5 mg 17β-E2 and 2.5 mg nomegestrol acetate, and four placebo pills. Studies conducted in Europe and the USA demonstrate that its Pearl index is 0.38 and 1.13, respectively. It has less influence on hemostasis, fibrinolysis markers, lipids and carbohydrate metabolism than the combined oral contraceptive levonorgestrel/EE (150 g/30 g and 100 µg/20 µg). Withdrawal bleedings are shorter and lighter as compared with women using drospirenone/EE (3 mg/ 30 µg). The number of women without withdrawal bleeding is approximately 30% after 12 months. Even though its contraindications are identical to other combined oral contraceptives, this nomegestrol acetate/E2 pill should be considered to be of interest for many women.

BACKGROUND Nomegestrol acetate/17β-estradiol (NOMAC/E(2)) is a new monophasic oral contraceptive combining NOMAC (2.5 mg), a highly selective progesterone-derived progestogen, with E(2) (1.5 mg), which is structurally identical to endogenous estrogen. The objective of this study was to compare the effects on ovarian activity of two different NOMAC/E(2) regimens. METHODS This was a double-blind, randomized study. Healthy, premenopausal women (aged 18-38 years, previous menstrual cycle length 28 ± 7 days) were randomized by computer-generated code to once-daily NOMAC/E(2) for three consecutive 28-day cycles: either 24 days with a 4-day placebo interval (n = 40) or 21 days with a 7-day placebo interval (n = 37) per cycle. Follicular growth (primary outcome measure), plasma hormone profiles and bleeding patterns were assessed. RESULTS There was no evidence of ovulation during treatment with either NOMAC/E(2) regimen. The largest follicle diameter was significantly smaller in the 24-day group than in the 21-day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (P = 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (P = 0.04)]. Mean FSH plasma levels were significantly lower in the 24-day versus the 21-day group on Day 24 of cycles 1 and 2. Withdrawal bleeding duration was significantly shorter in the 24-day than in the 21-day group [mean (SD) days after cycle 1: 3.5 (1.3) versus 5.0 (2.6) (P = 0.002); after cycle 2: 3.9 (1.6) versus 4.8 (1.7) (P = 0.03)]. CONCLUSIONS The 24-day NOMAC/E(2) regimen was associated with greater inhibition of follicular growth and shorter duration of withdrawal bleeding than the 21-day regimen, suggesting the shorter pill-free interval results in a greater margin of contraceptive efficacy and tolerability, and fewer withdrawal symptoms.

Objective: To explore the optimal dose of the progestogen, nomegestrol acetate (NOMAC), required in a monophasic oral contraceptive, in combination with 1.5 mg 17β-oestradiol (E(2)), to inhibit ovulation., Methods: A double-blind, randomised study assessing 41 normally cycling women (aged 18-35 years) over two screening cycles, one control cycle and one consecutive treatment cycle; 38 women completed the treatment period. Subjects received 0.625 mg NOMAC/1.5 mg E(2) (n = 9), 1.25 mg NOMAC/1.5 mg E(2) (n = 10), 2.5 mg NOMAC/1.5 mg E(2) (n = 10) or 2.5 mg NOMAC alone (n = 9) for 21 days., Results: During the treatment cycle, ovulation was suppressed in all treatment groups. The lowest plasma E(2) levels were observed with 2.5 mg NOMAC given alone. Addition of 1.5 mg E(2) to 2.5 mg NOMAC resulted in statistically significant increases in E(2) levels and decreases in mean follicle-stimulating hormone and luteinising hormone levels. In the three NOMAC/E(2) combination groups, a statistically significant inverse correlation was found between E(2) plasma levels and NOMAC dose., Conclusion: The dose of 2.5 mg NOMAC was confirmed to be optimal to inhibit both ovulation and follicular maturation. The antigonadotropic effect of 2.5 mg NOMAC was reinforced when combined with 1.5 mg E(2).

17 beta-Estradiol (E2) exerts negative feedback effects at the hypothalamo-pituitary level on serum FSH. This study investigated the effects of repeated daily administration of intranasal E2 (S21400) on the pharmacokinetics (PK) of E2 and estrone (E1) and the pharmacodynamics (PD) of FSH and assessed the PK/PD relationship between E2 and FSH using population model-dependent analysis. Postmenopausal volunteers (n = 24) received according to a balanced cross-over design, two 28-d treatments separated by a 2-month wash-out period: 300 microg E2, either alone or combined with oral dydrogesterone (20 mg/d) during the last 14 d of one of the treatments. Absorption of E2 was rapid, with maximal plasma concentrations at 10-30 min, returning to postmenopausal levels within 12 h. Over the 24-h period, FSH levels showed a U curve, with a minimum around 8 h after E2 administration. Moreover, over the treatment period, FSH basal values decreased by 17% between d 1 and 14 and an additional 5% between d 14 and 28. A PK/PD model described these short- and mid-term effects, possibly reflecting separate regulation mechanisms by E2 on FSH release and biosynthesis, respectively. The administration of progestin had no influence on E1, E2, and FSH model parameters. This study suggests that daily transient tissue exposure to E2 after pulsed estrogen therapy elicits short- and mid-term effects on the gonadotropin axis.

Aims: Women have a longer QT interval and a greater incidence of torsades de pointes than men. It has been suggested that oestrogens may influence the duration of cardiac repolarization. We thus investigated the influence of oestradiol (E2) on ventricular repolarization within the physiological concentration range of this hormone., Methods and Results: We studied QT interval duration in 21 healthy women aged 18 to 35 years with regular menstrual cycle (mean duration: 29+/-1 days) during two periods associated with a wide range of oestradiol plasma levels: low level during menses (105+/-34 pmol/l) and high level during the pre-ovulatory phase (750+/-277 pmol/l). We used heart rate-independent assessment of QT. QT-RR pairs were measured over a wide range of RR intervals obtained at rest and during a sub-maximal exercise test. Using a monoexponential nonlinear curve fitting for the QT-RR relation, the QT(1000 ms)during nadir and peak oestradiol periods was then determined for each subject. QT(1000 ms)interval was not different between both study periods: 382.1+/-18.4 ms at peak versus 382.2+/-19.4 ms at nadir oestradiol level (P=0.98)., Conclusion: No significant change in QT interval duration was observed within the large range of physiological E2 variations found during the menstrual cycle.

The roles of oestradiol, inhibin A and inhibin B in the luteal-follicular transition were assessed by means of specific assays. Six premenopausal women were studied during a control and then a cycle treated with percutaneous oestradiol 0.1 mg/day from day 10 after the luteinizing hormone (LH) surge until day 4 of the following cycle. Inhibin A concentrations decreased similarly in control and treated cycles from day -5 to day 2, then increased in control cycle to 23.3 +/- 3.4 pg/ml on day 10 (mean +/- SEM). They remained low until day 5 in treated cycles and were lower than controls on day 10 (P < 0.01). Follicle stimulating hormone (FSH) concentrations increased on day 1 in controls and on day 5 in treated cycles when oestradiol concentration fell abruptly. Inhibin B concentrations remained low until day 1 in controls and day 4 in treated cycles. In both, inhibin B concentrations increased 1 day after FSH, peaking at 160 pg/ml. FSH concentrations began to plateau when inhibin B concentrations were >100 pg/ml and oestradiol concentrations below 200 pmol/l. These data suggest that inhibin A is not responsible for FSH suppression in the luteal phase and that the negative control of FSH shifts from oestradiol in the luteal phase to inhibin B in the mid-follicular phase.