be due to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate. evaluating the response of breast tissue density to hrt using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed-dense breast tissue have a higher risk of developing breast cancer than those with low density tissue. micronized progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration. a retrospective cox proportional hazards analysis from richard neapolitan endorsed the reduced risk breast cancer with conjugated equine estrogen usage alone, but also suggested that conjugated equine estrogen with medroxyprogesterone acetate was associated with a risk reduction in breast cancer and that bioidentical hormone therapy was not associated with a statistically significant effect. there have been no prospective randomized clinical trials comparing the two routes of administration with regards to breast cancer. for women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonates or selective estrogen receptor modulators (serms) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms. observational studies of systemic hrt after breast cancer are generally reassuring. if hrt is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy. in women who are brca1 or brca2 mutation carriers, hrt does not appear to impact breast cancer risk. the relative number of women using hrt who also obtain regular screening mammograms is higher than that in women who do not use hrt, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups. with androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association. worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy (cghfbc, 2019) therapy <5 years 5–14 years 15+ years cases rr (95% ci) cases rr (95% ci) cases rr (95% ci) estrogen alone 1259 1.18 (1.10–1.26) 4869 1.33 (1.28–1.37) 2183 1.58 (1.51–1.67) by estrogen conjugated estrogens 481 1.22 (1.09–1.35) 1910 1.32 (1.25–1.39) 1179 1.68 (1.57–1.80) estradiol 346 1.20 (1.05–1.36) 1580 1.38 (1.30–1.46) 435 1.78 (1.58–1.99) estropipate (estrone sulfate) 9 1.45 (0.67–3.15) 50 1.09 (0.79–1.51) 28 1.53 (1.01–2.33) estriol 15 1.21 (0.68–2.14) 44 1.24 (0.89–1.73) 9 1.41 (0.67–2.93) other estrogens 15 0.98 (0.46–2.09) 21 0.98 (0.58–1.66) 5 0.77 (0.27–2.21) by route oral estrogens – – 3633 1.33 (1.27–1.38) – – transdermal estrogens – – 919 1.35 (1.25–1.46) – – vaginal estrogens – – 437 1.09 (0.97–1.23) – – estrogen and progestogen 2419 1.58 (1.51–1.67) 8319 2.08 (2.02–2.15) 1424 2.51 (2.34–2.68) by progestogen (levo)norgestrel 343 1.70 (1.49–1.94) 1735 2.12 (1.99–2.25) 219 2.69 (2.27–3.18) norethisterone acetate 650 1.61 (1.46–1.77) 2642 2.20 (2.09–2.32) 420 2.97 (2.60–3.39) medroxyprogesterone acetate 714 1.64 (1.50–1.79) 2012 2.07 (1.96–2.19) 411 2.71 (2.39–3.07) dydrogesterone 65 1.21 (0.90–1.61) 162 1.41 (1.17–1.71) 26 2.23 (1.32–3.76) progesterone 11 0.91 (0.47–1.78) 38 2.05 (1.38–3.06) 1 – promegestone 12 1.68 (0.85–3.31) 19 2.06 (1.19–3.56) 0 – nomegestrol acetate 8 1.60 (0.70–3.64) 14 1.38 (0.75–2.53) 0 – other progestogens 12 1.70 (0.86–3.38) 19 1.79 (1.05–3.05) 0 – by progestogen frequency continuous – – 3948 2.30 (2.21–2.40) – – intermittent – – 3467 1.93 (1.84–2.01) – – progestogen alone 98 1.37 (1.08–1.74) 107 1.39 (1.11–1.75) 30 2.10 (1.35–3.27) by progestogen medroxyprogesterone acetate 28 1.68 (1.06–2.66) 18 1.16 (0.68–1.98) 7 3.42 (1.26–9.30) norethisterone acetate 13 1.58 (0.77–3.24) 24 1.55 (0.88–2.74) 6 3.33 (0.81–13.8) dydrogesterone 3 2.30 (0.49–10.9) 11 3.31 (1.39–7.84) 0 – other progestogens 8 2.83 (1.04–7.68) 5 1.47 (0.47–4.56) 1 – miscellaneous tibolone – – 680 1.57 (1.43–1.72) – – notes: meta-analysis of worldwide epidemiological evidence on menopausal hormone therapy and breast cancer risk by the collaborative group on hormonal factors in breast cancer (cghfbc). fully adjusted relative risks for current versus never-users of menopausal hormone therapy. source: see template. risk of breast cancer with menopausal hormone therapy in large observational studies (mirkin, 2018) studytherapyhazard ratio (95% ci) e3n-epic: fournier et al. (2005)estrogen alone1.1 (0.8–1.6) estrogen plus progesterone transdermal estrogen oral estrogen0.9 (0.7–1.2)0.9 (0.7–1.2)no events estrogen plus progestin transdermal estrogen oral estrogen1.4 (1.2–1.7)1.4 (1.2–1.7)1.5 (1.1–1.9) e3n-epic: fournier et al. (2008)oral estrogen alone1.32 (0.76–2.29) oral estrogen plus progestogen progesterone dydrogesterone medrogestone chlormadinone acetate cyproterone acetate promegestone nomegestrol acetate norethisterone acetate medroxyprogesterone acetatenot analyzeda0.77 (0.36–1.62)2.74 (1.42–5.29)2.02 (1.00–4.06)2.57 (1.81–3.65)1.62 (0.94–2.82)1.10 (0.55–2.21)2.11 (1.56–2.86)1.48 (1.02–2.16) transdermal estrogen alone1.28 (0.98–1.69) transdermal estrogen plus progestogen progesterone dydrogesterone medrogestone chlormadinone acetate cyproterone acetate promegestone nomegestrol acetate norethisterone acetate medroxyprogesterone acetate1.08 (0.89–1.31)1.18 (0.95–1.48) 2.03 (1.39–2.97)1.48 (1.05–2.09)not analyzeda1.52 (1.19–1.96)1.60 (1.28–2.01)not analyzedanot analyzeda e3n-epic: fournier et al. (2014)estrogen alone1.17 (0.99–1.38) estrogen plus progesterone or dydrogesterone1.22 (1.11–1.35) estrogen plus progestin1.87 (1.71–2.04) cecile: cordina-duverger et al. (2013)estrogen alone1.19 (0.69–2.04) estrogen plus progestogen progesterone progestins progesterone derivatives testosterone derivatives1.33 (0.92–1.92)0.80 (0.44–1.43)1.72 (1.11–2.65)1.57 (0.99–2.49)3.35 (1.07–10.4) footnotes: a = not analyzed, fewer than 5 cases. sources: see template. risk of breast cancer with menopausal hormone therapy by duration in large observational studies (mirkin, 2018) studytherapyhazard ratio (95% ci) e3n-epic: fournier et al. (2005)atransdermal estrogen plus progesterone <2 years 2–4 years ≥4 years0.9 (0.6–1.4)0.7 (0.4–1.2)1.2 (0.7–2.0) transdermal estrogen plus progestin <2 years 2–4 years ≥4 years1.6 (1.3–2.0)1.4 (1.0–1.8)1.2 (0.8–1.7) oral estrogen plus progestin <2 years 2–4 years ≥4 years1.2 (0.9–1.8)1.6 (1.1–2.3)1.9 (1.2–3.2) e3n-epic: fournier et al. (2008)estrogen plus progesterone <2 years 2–4 years 4–6 years ≥6 years0.71 (0.44–1.14)0.95 (0.67–1.36)1.26 (0.87–1.82)1.22 (0.89–1.67) estrogen plus dydrogesterone <2 years 2–4 years 4–6 years ≥6 years0.84 (0.51–1.38)1.16 (0.79–1.71)1.28 (0.83–1.99)1.32 (0.93–1.86) estrogen plus other progestogens <2 years 2–4 years 4–6 years ≥6 years1.36 (1.07–1.72)1.59 (1.30–1.94)1.79 (1.44–2.23)1.95 (1.62–2.35) e3n-epic: fournier et al. (2014)estrogens plus progesterone or dydrogesterone <5 years ≥5 years1.13 (0.99–1.29)1.31 (1.15–1.48) estrogen plus other progestogens <5 years ≥5 years1.70 (1.50–1.91)2.02 (1.81–2.26) footnotes: a = oral estrogen plus progesterone was not analyzed because there was a low number of women who used this therapy. sources: see template. ovarian cancer hrt is associated with an increased risk of ovarian cancer, with women using hrt having about one additional case of ovarian cancer per 1,000 users. this risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping hrt. regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer. hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates. colorectal cancer in the whi, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. however, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones. in colorectal cancer survivors, usage of hrt is thought to lead to lower recurrence risk and overall mortality. cervical cancer there appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with hrt and a weak increase in adenocarcinoma. no studies have reported an increased risk of recurrence when hrt is used with cervical cancer survivors. sexual function