Editing Progesterone (section)

===Breasts===
{{See also|Breast development#Biochemistry}}

====Lobuloalveolar development====
Progesterone plays an important role in [[breast development]]. In conjunction with [[prolactin]], it mediates [[mammary alveolus|lobuloalveolar]] maturation of the [[mammary gland]]s during pregnancy to allow for milk production and thus [[lactation]] and [[breastfeeding]] of [[offspring]] following [[parturition]] (childbirth).<ref name="pmid22844349">{{cite journal | vauthors = Macias H, Hinck L | title = Mammary gland development | journal = Wiley Interdisciplinary Reviews. Developmental Biology | volume = 1 | issue = 4 | pages = 533–557 | year = 2012 | pmid = 22844349 | pmc = 3404495 | doi = 10.1002/wdev.35 }}</ref> [[Estrogen]] induces expression of the PR in breast tissue and hence progesterone is dependent on estrogen to mediate lobuloalveolar development.<ref name="pmid16917139" /><ref name="Johnson2003" /><ref name="CoadDunstall2011" /> It has been found that {{abbrlink|RANKL|Receptor activator of nuclear factor kappa-B ligand}} is a critical downstream mediator of progesterone-induced lobuloalveolar maturation.<ref name="pmid26266959">{{cite journal | vauthors = Hilton HN, Graham JD, Clarke CL | title = Minireview: Progesterone Regulation of Proliferation in the Normal Human Breast and in Breast Cancer: A Tale of Two Scenarios? | journal = Molecular Endocrinology | volume = 29 | issue = 9 | pages = 1230–1242 | date = September 2015 | pmid = 26266959 | pmc = 5414684 | doi = 10.1210/me.2015-1152 }}</ref> RANKL [[knockout mice]] show an almost identical mammary phenotype to PR knockout mice, including normal mammary ductal development but complete failure of the development of lobuloalveolar structures.<ref name="pmid26266959" />

====Ductal development====
Though to a far lesser extent than estrogen, which is the major mediator of mammary ductal development (via the [[estrogen receptor alpha|ERα]]),<ref name="StraussBarbieri2013">{{cite book|vauthors=Barbieri RL|chapter=The Breast|veditors=Strauss JF, Barbieri RL|title=Yen and Jaffe's Reproductive Endocrinology|chapter-url=https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA236|date=13 September 2013|publisher=Elsevier Health Sciences|isbn=978-1-4557-2758-2|pages=236–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025044/https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA236|url-status=live}}</ref><ref name="pmid24718936">{{cite journal | vauthors = Scaling AL, Prossnitz ER, Hathaway HJ | title = GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast | journal = Hormones & Cancer | volume = 5 | issue = 3 | pages = 146–160 | date = June 2014 | pmid = 24718936 | pmc = 4091989 | doi = 10.1007/s12672-014-0174-1 }}</ref> progesterone may be involved in ductal development of the mammary glands to some extent as well.<ref name="pmid23705924">{{cite journal | vauthors = Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ | title = Amphiregulin mediates progesterone-induced mammary ductal development during puberty | journal = Breast Cancer Research | volume = 15 | issue = 3 | pages = R44 | date = May 2013 | pmid = 23705924 | pmc = 3738150 | doi = 10.1186/bcr3431 | doi-access = free }}</ref> PR knockout mice or mice treated with the [[antiprogestogen|PR antagonist]] [[mifepristone]] show delayed although otherwise normal mammary ductal development at puberty.<ref name="pmid23705924" /> In addition, mice modified to have [[overexpression]] of [[progesterone receptor A|PRA]] display ductal hyperplasia,<ref name="pmid26266959" /> and progesterone induces ductal growth in the mouse mammary gland.<ref name="pmid23705924" /> Progesterone mediates ductal development mainly via induction of the [[gene expression|expression]] of [[amphiregulin]], the same [[growth factor]] that estrogen primarily induces the expression of to mediate ductal development.<ref name="pmid23705924" /> These animal findings suggest that, while not essential for full mammary ductal development, progesterone seems to play a potentiating or accelerating role in estrogen-mediated mammary ductal development.<ref name="pmid23705924" />

====Breast cancer risk====
Progesterone also appears to be involved in the [[pathophysiology]] of [[breast cancer]], though its role, and whether it is a promoter or inhibitor of breast cancer risk, has not been fully elucidated.<ref name="pmid23336704">{{cite journal | vauthors = Kuhl H, Schneider HP | title = Progesterone--promoter or inhibitor of breast cancer | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 54–68 | date = August 2013 | pmid = 23336704 | doi = 10.3109/13697137.2013.768806 | s2cid = 20808536 }}</ref><ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and Breast Cancer | journal = Endocrine Reviews | volume = 41 | issue = 2 | pages = 320–344 | date = April 2020 | pmid = 31512725 | pmc = 7156851 | doi = 10.1210/endrev/bnz001 }}</ref> Most [[progestin]]s, or [[synthetic compound|synthetic]] progestogens, like [[medroxyprogesterone acetate]], have been found to increase the risk of breast cancer in postmenopausal people in combination with estrogen as a component of [[menopausal hormone therapy]].<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="pmid31512725" /> The combination of natural oral progesterone or the atypical progestin [[dydrogesterone]] with estrogen has been associated with less risk of breast cancer than progestins plus estrogen.<ref name="pmid29384406">{{cite journal | vauthors = Stute P, Wildt L, Neulen J | title = The impact of micronized progesterone on breast cancer risk: a systematic review | journal = Climacteric | volume = 21 | issue = 2 | pages = 111–122 | date = April 2018 | pmid = 29384406 | doi = 10.1080/13697137.2017.1421925 | s2cid = 3642971 | doi-access = free | url = https://boris.unibe.ch/125894/1/29384406.pdf | access-date = 2 February 2024 | archive-date = 2 February 2024 | archive-url = https://web.archive.org/web/20240202143017/https://boris.unibe.ch/125894/1/29384406.pdf | url-status = live }}</ref><ref name="pmid27456847">{{cite journal | vauthors = Asi N, Mohammed K, Haydour Q, Gionfriddo MR, Vargas OL, Prokop LJ, Faubion SS, Murad MH | display-authors = 6 | title = Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | pages = 121 | date = July 2016 | pmid = 27456847 | pmc = 4960754 | doi = 10.1186/s13643-016-0294-5 | doi-access = free }}</ref><ref name="pmid29852797">{{cite journal | vauthors = Gompel A, Plu-Bureau G | title = Progesterone, progestins and the breast in menopause treatment | journal = Climacteric | volume = 21 | issue = 4 | pages = 326–332 | date = August 2018 | pmid = 29852797 | doi = 10.1080/13697137.2018.1476483 | s2cid = 46922084 }}</ref> However, this may simply be an artifact of the low progesterone levels produced with oral progesterone.<ref name="pmid23336704" /><ref name="pmid29526116">{{cite journal | vauthors = Davey DA | title = Menopausal hormone therapy: a better and safer future | journal = Climacteric | volume = 21 | issue = 5 | pages = 454–461 | date = October 2018 | pmid = 29526116 | doi = 10.1080/13697137.2018.1439915 | s2cid = 3850275 }}</ref> More research is needed on the role of progesterone in breast cancer.<ref name="pmid31512725" />