Table 4 Relationship between menstrual cycles, progesterone and breast cancer

Data supporting the MC hypothesis (includes P4 and E2)

Individuals without MCs due to genetic abnormalities appear to have no BC

Strong correlation between the reduction in MCs due to physiological, genetic and pathological effects (AN, POI) and a decrease in the lifetime risk to develop BC

Artificial MCs induced by COCs carry a comparable or even somewhat higher BC risk compared to the natural MC

Data supporting the specific P4 hypothesis

P4 is mutagenic for the breast, while estrogens and testosterone are not

Individuals with the CAIS syndrome have substantial E2 levels and female size and structure breasts, but no P4 and no BC

Individuals with the MRKH syndrome have no uterus and no BC, but normal P4, which could be explained by the absence of WNT4 gene activity

P-only contraception without endogenous ovarian estrogens carries a BC risk comparable to the natural MC or even somewhat higher

Estrogen-only MHT decreases BC incidence and mortality when started more than 5 years after menopause

High dose estrogen treatment of MtF transgenders induces normal female size and structure breasts with a very low BC risk

FtM transgenders treated long term with high doses of testosterone have a low BC risk which is comparable to cisgender males