Editing Progestogen (medication) (section)

===Breast cancer===
Estrogen alone, progestogen alone, and combined estrogen and progestogen therapy are all associated with increased risks of breast cancer when used in [[menopausal hormone therapy]] for [[perimenopausal|peri-]] and [[postmenopausal]] women relative to non-use.<ref name="pmid31474332">{{cite journal | title = Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence | journal = Lancet | volume = 394 | issue = 10204 | pages = 1159–1168 | date = September 2019 | pmid = 31474332 | pmc = 6891893 | doi = 10.1016/S0140-6736(19)31709-X | author1 = Collaborative Group on Hormonal Factors in Breast Cancer }}</ref><ref name="pmid27898258">{{cite journal | vauthors = Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D | title = Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis | journal = Gynecol. Endocrinol. | volume = 33 | issue = 2 | pages = 87–92 | year = 2017 | pmid = 27898258 | doi = 10.1080/09513590.2016.1248932 | s2cid = 205631264 }}</ref><ref name="pmid24485796">{{cite journal | vauthors = Lambrinoudaki I | title = Progestogens in postmenopausal hormone therapy and the risk of breast cancer | journal = Maturitas | volume = 77 | issue = 4 | pages = 311–7 | year = 2014 | pmid = 24485796 | doi = 10.1016/j.maturitas.2014.01.001 }}</ref> These risks are higher for combined estrogen and progestogen therapy than with estrogen alone or progestogen alone.<ref name="pmid31474332" /><ref name="pmid24485796" /> In addition to breast cancer risk, estrogen alone and estrogen plus progestogen therapy are associated with higher breast cancer [[mortality rate|mortality]].<ref name="pmid31474331">{{cite journal | vauthors = Beral V, Peto R, Pirie K, Reeves G | title = Menopausal hormone therapy and 20-year breast cancer mortality | journal = Lancet | volume = 394 | issue = 10204 | page = 1139 | date = September 2019 | pmid = 31474331 | doi = 10.1016/S0140-6736(19)32033-1 | doi-access = free }}</ref> With 20&nbsp;years of use, breast cancer incidence is about 1.5-fold higher with estrogen alone and about 2.5-fold higher with estrogen plus progestogen therapy relative to non-use.<ref name="pmid31474332" /> The increase in breast cancer risk with estrogen and progestogen therapy was shown to be causal with [[conjugated estrogens]] plus [[medroxyprogesterone acetate]] in the [[Women's Health Initiative]] [[randomized controlled trial]]s.<ref name="pmid29526116"/><ref name="pmid24291402">{{cite journal | vauthors = Stanczyk FZ, Bhavnani BR | title = Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: is it safe? | journal = J. Steroid Biochem. Mol. Biol. | volume = 142 | pages = 30–8 | date = July 2014 | pmid = 24291402 | doi = 10.1016/j.jsbmb.2013.11.011 | s2cid = 22731802 }}</ref>

Breast cancer risk with combined estrogen and progestogen therapy may differ depending on the progestogen used.<ref name="pmid27898258" /><ref name="pmid31474332" /><ref name="pmid23238854" /><ref name="pmid23651281" /> Progestins including [[chlormadinone acetate]], [[cyproterone acetate]], [[medrogestone]], [[medroxyprogesterone acetate]], [[nomegestrol acetate]], [[norethisterone acetate]], [[promegestone]], and [[tibolone]] have all been associated with similarly increased risk of breast cancer.<ref name="pmid23651281" /><ref name="pmid27898258" /><ref name="pmid31474332" /> Some research has found that [[oral progesterone]] and [[dydrogesterone]] with short-term use (<5&nbsp;years) may be associated with lower risk of breast cancer relative to other progestins.<ref name="pmid27898258" /><ref name="pmid31474332" /><ref name="pmid23238854" /><ref name="pmid23651281">{{cite journal | vauthors = Sturdee DW | title = Are progestins really necessary as part of a combined HRT regimen? | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 79–84 | date = August 2013 | pmid = 23651281 | doi = 10.3109/13697137.2013.803311 | s2cid = 21894200}}</ref> In the long-term however (>5&nbsp;years), oral progesterone and dydrogesterone have been associated with significantly increased breast cancer risk similarly to other progestogens.<ref name="pmid31474332" /><ref name="pmid29630427">{{cite journal | vauthors = Mirkin S | title = Evidence on the use of progesterone in menopausal hormone therapy | journal = Climacteric | volume = 21 | issue = 4 | pages = 346–354 | date = August 2018 | pmid = 29630427 | doi = 10.1080/13697137.2018.1455657 | doi-access = free}}</ref> The lower risk of breast cancer with oral progesterone than with other progestogens may be related to the very low progesterone levels and relatively weak progestogenic effects it produces.<ref name="pmid23336704" /><ref name="pmid29526116" /><ref name="Kuhl2011t" />

The risk of breast cancer with estrogen and progestogen therapy in peri- and postmenopausal women is dependent on the duration of treatment, with more than 5&nbsp;years of use being associated with significantly greater risk than less than five years of use.<ref name="pmid31474332" /><ref name="pmid27898258" /> In addition, continuous estrogen and progestogen therapy is associated with a higher risk of breast cancer than cyclic use.<ref name="pmid31474332" /><ref name="pmid27898258" />

A nationwide [[observational study]] found that [[transfeminine hormone therapy]] with estrogen plus high-dose [[cyproterone acetate]] was associated with a 46-fold increased risk of breast cancer in [[transgender women]] relative to the expected incidence for [[cisgender men]].<ref name="pmid31088823">{{cite journal | vauthors = de Blok CJ, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KM, Barbé E, Konings IR, den Heijer M | title = Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands | journal = BMJ | volume = 365 | pages = l1652 | date = May 2019 | pmid = 31088823 | pmc = 6515308 | doi = 10.1136/bmj.l1652 }}</ref><ref name="pmid31027551">{{cite journal | vauthors = de Blok CJ, Dreijerink KM, den Heijer M | title = Cancer Risk in Transgender People | journal = Endocrinol. Metab. Clin. North Am. | volume = 48 | issue = 2 | pages = 441–452 | date = June 2019 | pmid = 31027551 | doi = 10.1016/j.ecl.2019.02.005 | s2cid = 135382400 }}</ref><ref name="pmid31343858">{{cite journal | vauthors = Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, Nota NM, den Heijer M, Gooren LJ | title = Evaluation and Treatment of Gender-Dysphoric/Gender Incongruent Adults | year = 2000 |journal=Endotext [Internet] | pmid = 31343858 | url = https://www.ncbi.nlm.nih.gov/sites/books/NBK544426/}}</ref><ref name="pmid31516689">{{cite journal | vauthors = Iwamoto SJ, Defreyne J, Rothman MS, Van Schuylenbergh J, Van de Bruaene L, Motmans J, T'Sjoen G | title = Health considerations for transgender women and remaining unknowns: a narrative review | journal = Ther Adv Endocrinol Metab | volume = 10 | page = 2042018819871166 | date = 2019 | pmid = 31516689 | pmc = 6719479 | doi = 10.1177/2042018819871166 }}</ref> However, the risk of breast cancer was still lower than that in [[cisgender women]].<ref name="pmid31088823" /><ref name="pmid31027551" /><ref name="pmid31343858" /><ref name="pmid31516689" /> The extent to which the increase in breast cancer risk was related to estrogen versus cyproterone acetate is unknown.<ref name="pmid31088823" /><ref name="pmid31027551" /><ref name="pmid31343858" /><ref name="pmid31516689" />

{{Worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy}}

{{Risk of breast cancer with menopausal hormone therapy in large observational studies}}

{{Risk of breast cancer with menopausal hormone therapy by duration in large observational studies}}