Estetrol and Mammary Gland: Friends or Foes?

Abstract

Estrogens have pleiotropic effects on many reproductive and non-reproductive tissues and organs including the mammary gland, uterus, ovaries, vagina, and endothelium. Estrogen receptor α functions as the principal mediator of estrogenic action in most of these tissues. Estetrol (E4) is a native fetal estrogen with selective tissue actions that is currently approved for use as the estrogen component in a combined oral contraceptive and is being developed as a menopause hormone therapy (MHT, also known as hormone replacement therapy). However, exogenous hormonal treatments, in particular MHTs, have been shown to promote the growth of preexisting breast cancers and are associated with a variable risk of breast cancer depending on the treatment modality. Therefore, evaluating the safety of E4-based formulations on the breast forms a crucial part of the clinical development process. This review highlights preclinical and clinical studies that have assessed the effects of E4 and E4-progestogen combinations on the mammary gland and breast cancer, focusing in particular on the estrogenic and anti-estrogenic properties of E4. We discuss the potential advantages of E4 over current available estrogen-formulations as a contraceptive and for the treatment of symptoms due to menopause. We also consider the potential of E4 for the treatment of endocrine-resistant breast cancer.

Estetrol: A New Choice for Contraception

“…On breast tumor tissue it acts as an estrogen antagonist in the presence of E2 [ 21 , 22 ]. The estrogen-antagonistic effect of E4 in the breast has been further supported by a recent pre-clinical study that has been performed in women with breast cancer, finding that E4 reduces breast cancer cells proliferation [ 21 , 23 , 24 , 25 , 26 ]. These features could suggest a future role of E4 as a selective estrogen receptor modulator (SERM), but with less adverse effect than tamoxifen (hot flushes, nausea, hypertension, thromboembolic events, endometrial hyperplasia) [ 24 , 27 , 28 ].…”

Experts' view on the role of oestrogens in combined oral contraceptives: emphasis on oestetrol (E4)

“…Theoretically, due to its extended half-life and limited impact on the liver, E4 might effectively alleviate physical symptoms associated with PMS ( 94 ), such as breast tenderness, headaches, and water retention. Pre-clinical studies suggest that E4 may support vaginal health by promoting epithelial proliferation and lubrication ( 95 , 96 ). Combining E4 with DRSP also seems to have minimal impact on weight gain ( 97 , 98 ).…”

Estrogeni e infiammazione

“…È un estrogeno naturale di eccezionale interesse clinico: su tutte le cellule e i tessuti ha funzioni simili all’estradiolo con l’eccezione della mammella, sulla quale agisce in senso anti-estrogenico. Si ipotizza, quindi, che il suo ruolo principale sia la protezione delle cellule mammarie rispetto agli elevatissimi livelli di estradiolo caratteristici della gravidanza [ 22 ]. In virtù di questa sua azione anti-proliferativa selettiva sul tessuto mammario è oggetto di ricerca sia per la terapia ormonale sostitutiva in menopausa sia per la terapia anticoncezionale [ 23 , 24 ].…”