Table 1 Sex hormone-based differences in CRC

Estradiol/17β-estradiol (E2) Estrone

Human CRC tissue or blood sample (from postmenopausal women)

Endogenous estradiol and estrone levels are inversely associated with CRC risk and complication.

[16,17,18,19,20,21,22,23]

Pre-diagnostic estrogen and other sex steroid levels are positively associated with mortality risk in female CRC survivors.

[34]

Estradiol levels are not associated with CRC risk in postmenopausal women.

[36,37,38]

Pathobiological role of estrogen in postmenopausal CRC varies depending on patient age and tumor characteristics.

[42]

AOM/DSS, OVX_AOM/DSS, and OVX_Min/+ mice

Estradiol prevents colorectal carcinogenesis and metastasis by inhibiting inflammatory pathways, regulating Nrf2-related signaling, and ameliorating impaired associations with E-cadherin and β-catenin.

[26,27,28]

MC38 and OVX_MC38 tumor model mice

E2 inhibits MC38 tumor growth by regulating tumor-associated cell populations and reducing PD-L1 expression. Obesity, macrophage-associated inflammation, and TAMs are potential mechanisms for inducing CRC in females lacking estrogen.

[30, 31]

Estrogen is implicated in hepatic immunosuppression within the tumor microenvironment and promotes metastatic expansion.

[41]

AOM-male mice

DLD1, HT-29, SW480, SW620 cells and CSCs

E2 inhibits the migration and proliferation of DLD1 cells independently of miR-34a-mediated actions.

[24]

Combined use of E2 and progesterone treatment promotes cell cycle arrest and apoptosis by stimulating the expression of ERβ and PGR and inhibiting ERα-regulated oncogenic pathways.

[32, 33]

Combined use of E2 and 5-fluorouracil treatment exhibits superior anticancer effects than monotherapy on female and male primary CRC cells. E2 monotherapy exhibits the most substantial effects on male metastatic cells.

[33]

E2 induces the expression of estrogen receptors on CSCs, promoting their migration and metastasis.

[40]

ERβ

Human CRC, sporadic polyps, and FAP tissue

ERβ expression is reduced in colorectal precancerous stages and plays a key role in inhibiting the development of CRC.

[44, 45, 47,48,49]

AOM/DSS ERβ _KO mice

ERβ knockdown significantly induces TNFα expression and affects NF-κB inflammatory signals.

SW480 and HT-29 cells

Progesterone

PGR

Human CRC tissue or blood sample (from postmenopausal women)

Progesterone is generally not associated with CRC risk in postmenopausal women.

[16, 37, 38, 50]

Progesterone and PGR expression levels positively correlate with the prognosis of CRC.

[48, 51, 52]

Xenograft tumor model

Progesterone activates the GADD45α/JNK pathway, arrests the cell cycle, and induces apoptosis, thereby inhibiting CRC progression.

CRC cell lines

Testosterone

SHBG

Androstenedione DHEA

CRC/adenoma patients, tissue or blood samples

Higher levels of circulating testosterone and SHBG are associated with lower CRC risk, whereas free testosterone levels are positively associated with CRC risk.

[19, 37, 54,55,56,57]

Patients with prostate cancer who undergo androgen deprivation therapy have an increased risk of CRC

[58]

Free testosterone levels are negatively associated with CRC incidence and mortality in both men and women.

[34, 57, 60, 61]

Circulating concentrations of testosterone, SHBG, androstenedione, and DHEA are not associated with the risk of early precursor lesions in the colon or colon cancer

[38, 62, 63]

AOM/DSS and ORX_AOM/DSS mice

Testosterone enhances AOM/DSS-induced CRC development.

[8, 32]

Pirc/+ rat, Min/+ mice, and AOM mice

Sex differences in colon adenoma development may result from an indirect tumor-promoting effect of testosterone rather than a protective effect of estrogen.

[59]