H. J. T. Coelingh Bennink

Effects of Two Doses of Tibolone on Trabecular and Cortical Bone Loss in Early Postmenopausal Women: A Two-Year Randomized, Placebo-Controlled Study

The present randomized, double-blind, placebo-controlled, 2-year study is the first to evaluate the effect of 1.25 and 2.5 mg tibolone daily oral administration on trabecular and cortical bone loss in early postmenopausal women. Ninety-four healthy, normal weight, nonsmoking women participated 1-3 years following spontaneous menopause. Twenty-three subjects were randomized to the placebo group, 36 to the 1.25 mg/day tibolone group, and 35 to the 2.5 mg/day tibolone group. Bone density was assessed at 6 month intervals. Spinal trabecular bone density (BD) was measured with quantitative computed tomography. Phalangeal cortical BD was measured by radiographic absorptiometry. The 2-year change vs. baseline in the placebo group for trabecular BD was -6.4% (95% confidence interval -8.1 to -4.7). Cortical BD did not change significantly. At 24 months both tibolone groups showed a statistically significantly higher trabecular [9.4% (6.6-12.2) for the 1.25 mg group and 14.7% (11.8-17.5%) for the 2.5 mg group] and phalangeal BD [4.4% (1.5-7.4) for the 1.25 mg group and 6.8% (3.8-9.8) for the 2.5 mg group] as compared to the placebo group. After 2 years of tibolone in both regimes, trabecular and phalangeal BD was significantly higher as compared to pretreatment values. At 24 months the 2.5 mg group showed a significantly higher trabecular (p < 0.001) but not phalangeal (p = 0.064) BD compared to the 1.25 mg group. Tibolone prevents early postmenopausal bone loss by inducing an increase in trabecular and phalangeal BD.

Effects of tibolone on the endometrium

Objective To investigate the effects of 24 months of tibolone treatment on the endometrium in postmenopausal women. Design An open, prospective, multicenter study with a treatment duration of 24 months. Population One hundred and fifty healthy postmenopausal women. Methods Women were treated with one tablet of tibolone (2.5 mg Org OD14) daily. Endometrial biopsies were taken at baseline, 12 months (n = 112) and 24 months (n = 62) to investigate endometrial histology by means of light microscopy. Results No stimulation of atrophic endometrium was observed in 98.2% and 91.9% of the analyzed women after 12 and 24 months, respectively. A change from an atrophic endometrial pattern to a weakly proliferative pattern was seen in 1.8% (95% confidence interval (CI) 0.22–6.45) and 6.5% (95% CI 1.20–7.51) of the women after 12 and 24 months, respectively. In one woman, the endometrial pattern after 24 months was classified as simple hyperplasia (1.6%; 95% CI 0.01–3.20). The low incidence of proliferation and/or hyperplasia corresponds to that seen in other clinical trials in which women have been treated with placebo. Vaginal bleeding and/or spotting was reported by 18 women (12%), all showing an atrophic endometrium at all assessments, except for one woman with a proliferative endometrium at 24 months. Conclusion In the majority of women (92%), the endometrium remained atrophic during 24 months of tibolone treatment.

Dose–response analysis of effects of tibolone on climacteric symptoms

Objective To assess the clinically optimal tibolone dose for the relief of climacteric complaints.

A 4-year pilot study on the efficacy and safety of Implanon, a single-rod hormonal contraceptive implant, in healthy women in Thailand.

OBJECTIVE To investigate the contraceptive efficacy, safety and acceptability of a new single-rod, progestogen-only contraceptive implant (Implanon). METHODS In an open, non-comparative pilot study, 100 healthy women received a contraceptive implant containing the progestogen etonogestrel (3-ketodesogestrel) for 2 years with an optional extension up to 4 years. RESULTS Subjects were exposed to Implanon for 296.1 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding-spotting days was 10 and the median number of bleeding-spotting episodes was 2. Amenorrhea occurred in 24-39% of subject during the first 2 years and in about 20% in those who continued in the 3rd and 4th years. The most common drug-related adverse event was headache (7%). A slight increase in body mass index was observed. Only a few subjects discontinued treatment early, due to bleeding irregularities (6%) or amenorrhea (1%). The cumulative discontinuation rates were 13.4% after 2 years, 25.3% after 3 years and 28.0% after 4 years of use. Within 3 months of implant removal, six normal pregnancies occurred, indicating a rapid return of fertility. The average time taken for insertion of the implant was 0.5 min, compared with 2.5 min for removal. CONCLUSIONS Implanon demonstrated excellent contraceptive efficacy and was well tolerated during up to 4 years of use. The vaginal bleeding pattern was variable and was characterized by relatively few bleeding events, but proved acceptable to most subjects. Because of its single-rod design, Implanon was quickly inserted and removed without complications.

A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 μg desogestrel or 30 μg levonorgestrel

Abstract The effects of two progestogen-only pills containing either 75 μg desogestrel (DSG) or 30 μg levonorgestrel (LNG) on hemostasis were investigated in a double-blind, randomized, controlled study of seven treatment cycles in 78 healthy women. DSG reduced factor VII activity (p Both preparations had comparable and potentially favorable effects on hemostasis, and may offer suitable hormonal contraception to women with a personal or family history of venous thromboembolic diseases.

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.

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

Objectives To measure the oral bioavailability of estetrol (E4) in rats relative to its subcutaneous administration and to test the bone-sparing effect of oral E4 compared to that of ethinylestradiol (EE). Methods In the bioavailability study, E4 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 + E4 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 E4, relative to that of subcutaneous dosing, was 70% and above at the 0.05 and 0.5 mg/kg doses based on the AUC0-t last. Subcutaneous dosing provided significantly higher E4 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, E4 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 E4 (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 E4 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, E4 may be superior to other estrogens and is a potential drug for the prevention of osteoporosis in postmenopausal women.

Preventive effect of oral estetrol in a menopausal hot flush model

Objective To evaluate the efficacy of estetrol (E4) in alleviating hot flushes in an experimental animal model considered representative for menopausal vasomotor symptoms. Methods Recording of the thermal responses in the tail skin of morphine-dependent ovariectomized rats after morphine withdrawal by administration of naloxone. Six groups of rats were treated orally for 8 days as follows: vehicle (negative) control; E4: 0.1, 0.3, 1.0 and 3.0 mg/kg/day; and, as active (positive) control, ethinylestradiol 0.3 mg/kg/day. On day 8, tail skin temperature was recorded at baseline and for 60 min at 5-min intervals following naloxone administration. Results In control animals, tail skin temperature increased sharply by about 4.5°C after naloxone treatment and reverted to baseline by 60 min. Estetrol suppressed the tail skin temperature increase in a dose-dependent fashion. The highest dose of E4 tested (3 mg/kg/day) was equipotent to a 10-fold lower dose of ethinylestradiol. Both fully suppressed tail skin temperature changes. Conclusion Estetrol is effective in alleviating hot flushes in an experimental animal model considered representative for studying menopausal hot flushes (vasomotor symptoms). In this model, the potency of estetrol is 10-fold lower compared to ethinylestradiol.

Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells

Objectives To determine whether human sex hormone binding globulin (SHBG) binds estetrol (E4), and to assess whether E4 stimulates the production of SHBG by human hepatocytes. Methods Competitive ligand binding assays have been used to assess the relative binding affinity of E4 to human SHBG using either [3H]5α-dihydrotestosterone or [3H]estradiol as labeled ligands. The effect of E4 on the production of SHBG has been assessed by a fluoroimmunometric assay in wild-type human HepG2 cells and in human Hep89 cells that over-express the human estrogen receptor (ER) α, and compared to the effect of ethinylestradiol, estradiol and estriol. Results There was no detectable binding of E4 to the human SHBG steroid-binding sites. By contrast, testosterone and estradiol were bound with high affinity and the synthetic estrogen ethinylestradiol was found to bind SHBG with low affinity. Estetrol does not stimulate ERα-mediated increases in SHBG production by HepG2 or Hep89 cells, in contrast to ethinylestradiol, estradiol and estriol. Conclusions These data indicate that SHBG has no influence on the plasma distribution of E4 or its availability to target tissues. In addition, it is shown that E4 has no effect on SHBG production by human hepatocytes.

FSH and ovarian response: spontaneous recovery of pituitary-ovarian activity during the pill-free period vs. exogenous recombinant FSH during high-dose combined oral contraceptives.

ojbective Compare spontaneous recovery of pituitary–ovarian activity during the pill‐free period following the correct use of low‐dose oral contraceptives and subsequent ovarian function during the administration of exogenous recombinant FSH (recFSH) after switching to continued Lyndiol® (2·5 mg lynestrenol + 0·05 mg ethinyl‐oestradiol) medication.