Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women.

OBJECTIVES: Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary objective. METHODS: In total, 49 postmenopausal women were randomized to receive either 2 mg E4 or 2 mg estradiol valerate (E2V) for 28 days, or were (non-randomized) assigned to 10, 20, or 40 mg E4. The main outcome measures were: E4 plasma concentrations at trough, and on days 1 and 28; and E4 pharmacokinetic parameters AUC, Cmax and tmax on days 1 and 28. RESULTS: After oral administration, E4 showed a very fast absorption, followed by a multiphasic elimination with an initial rapid decline, gradually continuing with a slower elimination, suggesting a long terminal half-life. Steady state was reached within 2 weeks of dosing and pharmacokinetic results were generally proportional to the dose. Estetrol concentrations on day 28 were slightly higher compared to day 1, indicating some accumulation. CONCLUSION: The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.

Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives.

OBJECTIVES: Estetrol (E4) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E4 blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E4/DRSP and E4/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters. METHODS: This was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E4/3 mg DRSP; 5 mg, 10 mg or 20 mg E4/150 µg LNG; or 20 µg EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated. RESULTS: A total of 109 women were included in the study. Carrier proteins were minimally affected in the E4/DRSP and E4/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E4 groups, and the effects on triglycerides elicited by the E4 groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E4 groups. CONCLUSIONS: E4-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters.

Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model.

OBJECTIVES: To measure the oral bioavailability of estetrol (E(4)) in rats relative to its subcutaneous administration and to test the bone-sparing effect of oral E(4) compared to that of ethinylestradiol (EE). METHODS: In the bioavailability study, E(4) was administered as a single dose of 0.05, 0.5 or 5.0 mg/kg orally or subcutaneously to female rats. Plasma was analyzed using an LC-MS/MS method. The bone study was conducted in 3-month-old female rats assigned to the following seven treatment groups of ten animals each: no treatment; sham-operated + vehicle; bilaterally ovariectomized (OVX) + vehicle; OVX + E(4) 0.1, 0.5, or 2.5 mg/kg/day and OVX + EE 0.1 mg/kg/day. Once-daily treatment by oral gavage was given for 4 weeks and the following measurements were performed: serum osteocalcin, bone mineral density, bone mineral content and bone mineral area of lumbar vertebrae L3-L6, peripheral quantitative computed tomography of the left tibiae and the biomechanical properties of the distal femora. RESULTS: Oral bioavailability of E(4), relative to that of subcutaneous dosing, was 70% and above at the 0.05 and 0.5 mg/kg doses based on the AUC(0-t last). Subcutaneous dosing provided significantly higher E(4) levels at the 1-h time point only, and was comparable to oral dosing after 0.5, 2, 4 and 8 h. In the bone study, E(4) dose-dependently and significantly (1) inhibited the OVX-related increase in osteocalcin levels, (2) increased bone mineral density and content, and (3) increased bone strength, all attenuated by ovariectomy. In this rat model, the relative potency of the highest dose of E(4) (2.5 mg/kg/day) was comparable to the EE dose, used as positive control. CONCLUSIONS: Estetrol exhibits high oral bioavailability in the rat, a species considered relevant for pharmacological studies that are predictive for effects on human bone. Oral administration of E(4) conveys dose-dependent bone-sparing effects of high-quality bone in estrogen-depleted OVX rats. Based on its bone-sparing effects, its oral bioavailability and its preclinical safety and efficacy profile, E(4) may be superior to other estrogens and is a potential drug for the prevention of osteoporosis in postmenopausal women.

First human exposure to exogenous single-dose oral estetrol in early postmenopausal women.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics and effect on gonadotropins of a single escalating dose of estetrol (E(4)). METHODS: A first-in-human study with E(4) was performed in healthy early postmenopausal women. Four single doses of 0.1, 1, 10 and 100 mg E(4) were evaluated in study groups of eight subjects each, of whom six received active treatment and two placebo treatment. Safety and tolerability were documented and several pharmacokinetic parameters were determined, as were the plasma levels of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) (pharmacodynamics). The next higher-dose group was enrolled after pharmacokinetic evaluation and confirmed safety of the previous group. RESULTS: After oral intake, the plasma concentrations of E(4) showed a steep increase, followed by a sharp decline and a secondary increase at all dose levels. Estetrol was distributed and reabsorbed during the first 18 h after oral intake. The terminal elimination phase started at 24 h post-dose and half-life (t((1/2))) ranged in the 10 mg group between 19 and 40 h (mean 28.4 h, median 28.8 h) and in the 100 mg group between 18 and 60 h (mean 28.0 h, median 20 h), indicating a dose independency of the half-life. The pharmacokinetic parameters also demonstrated a high dose-response relationship and showed excellent consistency and low variability within the dose groups. The pharmacodynamic data showed a dose-dependent inhibition of plasma LH levels by E(4). A profound and sustained inhibition of FSH levels, lasting over 168 h, was observed in the 100 mg dose group (FSH was not measured in the other dose groups). Estetrol was well tolerated at all dose levels and no safety problems were encountered. CONCLUSIONS: Estetrol is orally absorbed and bioavailable with a strong dose-response relationship suggesting high oral bioavailability. Interindividual variations of plasma levels are low. The elimination half-life of 28 h suggests slow metabolism of E(4). The pharmacodynamic pattern complies with enterohepatic recirculation. Estetrol has a profound central inhibitory and dose-dependent effect on gonadotropins, confirming its biological potency.

Estetrol review: profile and potential clinical applications.

In this review paper, the existing information on the human fetal steroid estetrol (E4) has been summarized. In the past, E4 was considered as a weak estrogen and interest disappeared. However, recent new research has demonstrated that E4 is a potent, orally bioavailable, natural human fetal selective estrogen receptor modulator, since it acts in the rat as an estrogen on all tissues investigated except breast tumor tissue, where it has estrogen antagonistic properties in the presence of estradiol. Based on its safety data, its pharmacokinetic properties, its pharmacological profile and the results of first human studies, E4 may be suitable as a potential drug for human use in applications such as hormone replacement therapy (vaginal atrophy, hot flushes), contraception and osteoporosis. Additional areas worth exploring are the treatment of breast and prostate cancer, hypoactive sexual desire disorder and topical use (wrinkles) in women, auto-immune diseases, migraine, cardiovascular applications and the treatment of selected obstetric disorders.