Menopause Hormone Therapy in Women With Cardiovascular Risk Factors or Established Ischemic Heart Disease: A Joint FIGO and WHF Position Paper

- ↑ endothelial production of prostacyclin and nitric oxide synthase activation (31, 32, 33)

- ↓ endothelin synthesis (31)

- Block of calcium channels (31)

- ↑ HDL-cholesterol efflux capacity (33, 34)

- ↓ LDL-cholesterol, ↓ triglyceride, ↓ lipoprotein Lp(a) (31, 35, 36)

- Regulation of mitochondrial function, which has a pivotal role in maintaining cardiometabolic health (37, 38)

- ↑ sirtuin transcription through ERα, in particular SIRT3, which reduces reactive oxygen species (ROS) in the mitochondria (39, 40)

- ↓inflammatory molecules and cell adhesion particles (31)

- ↓ vascular smooth muscle cell differentiation (41)

- ↓ vascular calcification (42)

- ↑ endothelial cell migration, proliferation and survival (43)

- ↑ vascular endothelial growth factor (VEGF) expression in endothelial cells (43)

- Prevention of cardiac fibrosis and detrimental myocardial extracellular matrix remodeling by modulating fibroblast proliferation and suppressing pro-fibrotic genes (32)

- ↑ active form of bradykinin promoting nitric oxide (NO) production and vasodilation (31, 44)

- Modulation of circadian metabolic rhythms, influencing the expression of various circadian genes through Estrogen Response Element (ERE) (45). Circadian rhythms affect cardiovascular function and therefore CVD susceptibility (46).

- Cigarette smoking

- Too vigorous physical exercise

- Low lifelong sun exposure

- Moderate alcohol consumption

- Regular tea consumption

- Moderate physical activity

- Vegetarian diet

- High polyunsaturated fat intake

- Caloric restriction particularly in childhood

- High total caloric intake

- High fruit and vegetables intake

- High protein and carbohydrate intake

- Lower education level

- Unemployment

- Higher educational attainment

- Being employed

- Nulliparity

- Parity

- BRCA mutations

- Japanese ethnicity

- History of heart disease

- Cardiac risk factors

- Increased epigenetic age

- Higher BMI in early adulthood

- Prior oral contraceptive use

↓ vasomotor symptoms (219, 224)

↑ sleep quality, especially in patients suffering from concomitant vasomotor symptoms (225)

↓ depressive symptoms, when MHT is used alone or in combination with antidepressants (226, 227)

↓ genitourinary symptoms (228)

↓ urinary tract infections (229)

↑ sexual function (10, 230, 231)

↓ biological aging (174, 232)

↓ all-cause mortality when MHT is started <10 years after menopause or in women <60 years old (221, 222, 233, 234, 235)

↓ composite of death from cardiovascular causes and non-fatal myocardial infarction when MHT is started <10 years after menopause or in women <60 years old (221)

↑ high density lipoprotein (10)

↓ insulin resistance and the incidence of diabetes (10)

↓ osteoporosis, bone loss and fracture risk at all sites (236)

↓ sarcopenia risk in physically active women (237)

↓ colorectal cancer risk, especially in women with a high polygenic risk score (238, 239)

↓ endometrial cancer risk with continuous use of combined estrogen-progestin, particularly in obese women (240, 241)

↓ breast cancer risk with estrogen-alone therapy, especially with CEE (242)

↑ cognitive performance when MHT, with the exception of CEE-MPA (243), is started in the peri-menopausal or early post-menopausal period (244, 245)

↓ Alzheimer’s Disease risk, particularly in APOE4 carriers (246) when MHT is started <10 years after menopause (247)

↑ VTE risk only with specific types of MHT i.e. oral estrogen alone or combined; transdermal estradiol combined with norpregnane, pregnane or nortestosterone derivatives (248, 249, 250) whenever it is started (221)

↑ ischemic stroke risk with specific types of MHT, i.e. oral estradiol, especially at high doses; CEE, especially at intermediate-high doses or when initiated >10 years after menopause; norpregnane derivatives; tibolone (221, 222, 251, 252, 253, 254)

↑ hemorrhagic stroke risk with specific types of MHT, i.e. tibolone (253)

↑ urinary incontinence and pre-existing pelvic organ prolapse (255, 256)

↑ breast cancer risk with specific types of MHT, i.e. estrogens combined with levonorgestrel/norethisterone acetate/medroxyprogesterone acetate, especially for long-term (257) or tibolone if taken for >5 years (10)

↑ endometrial cancer risk if systemic estrogen-alone therapy is given to women with an intact uterus (258)

↑ serous and endometrioid ovarian cancer risk with specific types of MHT, i.e. estrogen-alone or estrogen-progestogen preparations (259, 260)

↑ serous and all epithelial ovarian cancer risk with tibolone used for >10 years (261)

↓ cognitive function when MHT is started in older postmenopausal women (243)

= VTE risk with transdermal estradiol alone or transdermal estradiol + progesterone (250)

= or even ↓ ischemic stroke risk with transdermal estradiol (251, 253, 254)

= hemorrhagic stroke risk with transdermal estradiol (253)

= or even ↓ hemorrhagic stroke risk with oral estradiol and CEE (253, 262)

= breast cancer risk with estradiol + progesterone or dydrogesterone (263)

= mammographic breast density and breast cancer incidence risk with BZA/CE (264)

= breast cancer risk with Tibolone used for <5 years (263)

= survival from overall breast cancer with MHT (265)

= triglyceride levels with transdermal MHT, including estrogen alone and estrogen + progestogen (266)

= mucinous and clear cell ovarian cancers with estrogen only and estrogen-progestogen therapy (259, 260)

= lung cancer incidence risk and survival with MHT (220)