The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males

Abstract

The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.

Keywords: androgen deprivation therapy (ADT); bone loss; estetrol (E4); estrogen deficiency symptoms; hot flashes; transdermal estradiol (tE2).

Figure 1.

Mean levels of estradiol (E2 pg/mL), progesterone (P4 ng/mL), and testosterone (T pg/mL) during a normal menstrual cycle of 28 days, and corresponding E2 levels in postmenopausal women and in men (red bar) and T levels in men (blue bar). Original figure (sources: Frederiksen et al 2020, and Penell et al 2021) [11, 12].

Figure 2.

Median levels of (A) total testosterone, (B) free testosterone, and (C) prostate-specific antigen (PSA) after 2, 4, 6, 8, 12, 18, and 24 weeks of treatment with 40 mg estetrol (E4) or placebo in patients with prostate cancer treated with a GnRH agonist [6]. Note: E2, estradiol; P4, progesterone; T, testosterone. Adapted from Coelingh Bennink et al 2021 (reproduced according to BY-NC-ND 4.0) [6].