Abstract


Estetrol (E4) is an estrogen, produced exclusively by the human fetal liver during pregnancy. This steroid is orally bioavailable and has little interaction with the liver. E4 has few side effects and can therefore be administered at high doses. At present E4 is in phase 3 development for oral contraception and in phase 2 for the (add-back) treatment of breast cancer and for menopausal hormone treatment. view more

Estetrol (E4) is an estrogen, produced exclusively by the human fetal liver during pregnancy. This steroid is orally bioavailable and has little interaction with the liver. E4 has few side effects and can therefore be administered at high doses. At present E4 is in phase 3 development for oral contraception and in phase 2 for the (add-back) treatment of breast cancer and for menopausal hormone treatment. This study in healthy middle-aged men was performed to investigate the efficacy and safety of E4 for its potential use in the treatment of prostate cancer with special emphasis on the effect of E4 on testosterone levels.
This single-centre (QPS, Groningen, NL) double-blind, randomized, placebo-controlled, multiple dose study is conducted in healthy men (40-70 years). The allocation ratio between E4 and placebo treatment is 2:1 for each cohort of 15 volunteers. The first cohort received daily a single dose of 20 mg E4 and the second cohort 40 mg E4. A third cohort of 15 volunteers receiving 60 mg E4 is presently ongoing. Endocrine efficacy parameters include total testosterone by LC/MS, free testosterone by equilibrium dialysis, SHBG, LH, FSH, and E2 at baseline and after 14 and 28 days. Biochemical safety parameters included variables of hemostasis, lipids, glucose and bone turnover measured at baseline and after 28 days. Clinical safety parameters included body weight, vital signs, ECG, physical examination, routine laboratory tests and monitoring of (serious) adverse events. Here we report the endocrine and clinical safety results.
To date all 30 subjects from the first two cohorts completed the study. The statistical analysis will be performed after completion of the 60 mg E4 group and will be reported at the time of the meeting. With E4, total and free testosterone both decreased (Total T absolute change: -1.12 ± 4.36 nmol/L; -3.73 ± 3.27 nmol/L; -11.0 ± 5.47 nmol/L for placebo, 20 mg E4 and 40 mg E4 respectively and free T absolute change: -0.003 ± 0.061 nmol/L; -0.059 ± 0.030 nmol/L; -0.097 ± 0.027 nmol/L for placebo, 20 mg E4 and 40 mg E4 respectively). The levels of FSH and E2 levels also decreased, LH levels did not change and SHBG levels increased. The changes observed suggest dose-dependency. No clinical relevant changes in safety parameters and body weight were observed. During treatment with E4 libido decreased in 8 of 20 men and nipple tenderness was reported by 7 of 20 men, but these complaints were not dose-related.
Based on these results we conclude that a daily dose of 20 mg or 40 mg E4 for 28 days is well tolerated by healthy men aged 40 – 70 years. Libido decrease and nipple tenderness are the side effects most frequently reported. Overall, the observed dose-response related decrease of total and free testosterone levels and the acceptable safety parameters suggest that E4 may be suitable for the treatment of prostate cancer, both as estrogen add-back during Androgen Deprivation Therapy (ADT) and as primary ADT.

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