On May 30, 2023 the leading scientific journal dealing with basic and clinical breast cancer research “Breast Cancer Research (BCR)” published the Perspective Review paper  “Progesterone from ovulatory menstrual cycles is an important cause of breast cancer” by Herjan J.T. Coelingh Bennink, Iman J. Schultz, Marcus Schmidt, V. Craig Jordan, Paula Briggs, Jan F.M. Egberts, Kristina Gemzell-Danielsson, Ludwig Kiesel, Kirsten Kluivers, Jan Krijgh, Tommaso Simoncini, Frank Z. Stanczyk and Robert D. Langer.

The most important message of this narrative review paper is that progesterone from normal menstrual cycles causes most BCs, whereas estrogens and androgens may stimulate existing hormone receptor positive BC, but do not cause BC. Four authors of this paper are related to Pantarhei (HCB, IJS, JFME and JK) and the other nine authors are experts in the field of Reproductive Endocrinology and Oncology, supporting this rather thought-provoking paper, that will hopefully lead to a reappraisal and a turnaround of the medical view and opinion on the cause of breast cancer and change the negative perception of estrogens.

Abstract: Many factors, including reproductive hormones, have been linked to a woman’s risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumours tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman’s lifetime risk of developing BC, and that breast tumours arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.

Pantarhei Oncology announces the publication of its scientific paper “Testosterone suppression combined with high-dose estrogen as potential treatment of serious COVID-19 infection” (Heliyon 8 (2022) e12376)

COVID-19 infections are more serious and have a higher mortality in males compared to females especially at ages above 50 years. This is related to the 10-20x higher testosterone (T) levels in males. Suppression of T in males with serious COVID-19 has no consistent effect on the clinical outcome. However, by suppressing T in males, also their estrogen levels are decreased while estrogens have a favorable inhibitory effect on the factors responsible for the COVID-19 infection. Therefore, we hypothesize that a combination of T suppression by androgen-deprivation therapy (ADT) and high-dose estrogen (HDE) treatment may be an effective treatment of serious COVID-19, to be confirmed in in seriously ill COVID-19 patients.

The scientific background of this hypothesis

Most studies report a higher incidence of serious COVID-19 infections in males compared to females especially at ages above 50 years, which may be due to sex-related immunomodulation. A resulting higher mortality rate has been published in Maturitas, both in a meta-analysis performed in May 2020 and in a recent retrospective analysis. These observations could be associated with the 10-20x higher testosterone level in males, since testosterone has unfavourable effects on the immune system, and also stimulates angiotensin converting enzyme-2 (ACE2) and the androgen-regulated protease transmembrane protease serine 2 (TMPRSS2), which both facilitate the entry of the COVID-19 virus into the cell. Testosterone suppression by ADT decreases the effects of ACE2 and TMPRSS2. Estrogen treatment (ET) has the same beneficial suppressive effect on ACE2 and TMPRSS2 as ADT. Both ADT and ET (ADET) have been investigated separately as possible treatments of SARS-CoV-2. We hypothesize that the ADET combination may be more effective than its components alone, as also suggested in our Research Letter in European Urology (2021), entitled ‘Treatment of Serious COVID-19 with Testosterone Suppression and High-dose Estrogen (HDE) Therapy‘. The ADET co-treatment has been investigated successfully by Pantarhei Oncology in patients with advanced prostate cancer (Eur Urol Open Science, 2021 & 2022). We searched the literature for evidence of COVID-19 treatment benefits with estrogens, progesterone, androgen deprivation, and anti-androgens. Data supporting the effect of ADT on SARS-CoV-2 are sparse, but the favorable effects of estrogens in relation to COVID-19 have been shown in various cohort studies.

Based on the outcome of our review and the mode of action of the ADET combination, we hypothesize that a combination of ADT and HDE may be an effective and safe treatment of serious SARS-CoV-2 and we propose to test this ADET hypothesis in a clinical trial.

Pantarhei Oncology proudly announces that its paper ‘Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study’ has been published in the journal European Urology Open Science after comprehensive review. This journal is an international peer-reviewed, scientific, open access journal in the field of urology.

This paper summarises the very important data on the beneficial effects of high dose estetrol (HDE4) on the Quality of Life of prostate cancer patients treated with androgen deprivation therapy (ADT).