Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Dydrogesterone: Difference between pages

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Distinguish|Retroprogesterone}}

| Watchedfields = changed

| verifiedrevid = 461091780

| drug_name = Dydrogesterone

| type =

| IUPAC_name = (8''S'',9''R'',10''S'',13''S'',14''S'',17''S'')-17-acetyl-10,13-dimethyl-1,2,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthren-3-one

| image = Dydrogesterone.svg

| width = 225px

| image2 = Dydrogesterone molecule ball.png

| width2 = 235px

<!--Clinical data-->| tradename = Duphaston, others<ref name="brands" />

| Drugs.com = {{drugs.com|international|dydrogesterone}}

| pregnancy_category =

| legal_status = Rx-only

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Progestogen (medication)|Progestogen]]; [[Progestin]]

<!--Pharmacokinetic data-->| bioavailability = 28%<ref name="Femoston-Label" /><ref name="Schindler2015">{{cite book| vauthors = Schindler AE |title=Progestogens in Obstetrics and Gynecology|chapter=Pharmacology of Progestogens|year=2015|pages=33–40|publisher=Springer |doi=10.1007/978-3-319-14385-9_2|isbn=978-3-319-14384-2|s2cid=85844034 }}</ref>

| protein_bound = ? (probably to [[human serum albumin|albumin]])<ref name="FRCOG2015">{{cite book|vauthors = ((Howard J.A. Carp, MB, BS, FRCOG))|title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA33|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=33, 38}}</ref><ref name="pmid16112947" />

| metabolism = [[Liver|Hepatic]]: [[AKR1C1]], [[AKR1C3]], [[CYP3A4]]<ref name="OlbrichWeigl2016">{{cite journal | vauthors = Olbrich M, Weigl K, Kahler E, Mihara K | title = Dydrogesterone metabolism in human liver by aldo-keto reductases and cytochrome P450 enzymes | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 46 | issue = 10 | pages = 868–74 | date = October 2016 | pmid = 26796435 | doi = 10.3109/00498254.2015.1134852 | s2cid = 22311056 }}</ref><ref name="BeraničGobec2011">{{cite journal | vauthors = Beranič N, Gobec S, Rižner TL | title = Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 | journal = Chemico-Biological Interactions | volume = 191 | issue = 1–3 | pages = 227–33 | date = May 2011 | pmid = 21182831 | doi = 10.1016/j.cbi.2010.12.012 | bibcode = 2011CBI...191..227B }}</ref>

| metabolites = {{abbrlink|20α-DHD|20α-Dihydrodydrogesterone}} (exclusively via AKR1C1 and AKRC13)<ref name="BeraničGobec2011" />

| elimination_half-life = {{abbr|Parent|Dydrogesterone}}: 5–7 hours<ref name="BińkowskaWoroń2015">{{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = Przeglad Menopauzalny = Menopause Review | volume = 14 | issue = 2 | pages = 134–43 | date = June 2015 | pmid = 26327902 | pmc = 4498031 | doi = 10.5114/pm.2015.52154 }}</ref><br />{{abbr|Metabolite|20α-Dihydrodydrogesterone}}: 14–17 hours<ref name="BińkowskaWoroń2015" />

| excretion = [[Urine]]

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 152-62-5

| CAS_supplemental =

| ATC_prefix = G03

| ATC_suffix = DB01

| PubChem = 9051

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00378

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 8699

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 90I02KLE8K

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01217

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 31527

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| synonyms = Isopregnenone; Dehydroprogesterone; Didrogesteron; 6-Dehydroretroprogesterone; 9β,10α-Pregna-4,6-diene-3,20-dione; NSC-92336<ref name="Elks2014" /><ref name="IndexNominum2000" />

<!--Chemical data-->| C = 21

| H = 28

| O = 2

| SMILES = O=C4\C=C3\C=C/[C@@H]1[C@@H](CC[C@@]2([C@@H](C(=O)C)CC[C@@H]12)C)[C@]3(C)CC4

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C21H28O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h4-5,12,16-19H,6-11H2,1-3H3/t16-,17+,18-,19+,20+,21+/m0/s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = JGMOKGBVKVMRFX-HQZYFCCVSA-N

<!--Physical data-->| melting_point = 144

| boiling_point = 463

| solubility = Insoluble

<!-- Definition and medical uses -->

'''Dydrogesterone''', sold under the brand name '''Duphaston''' among others,<ref name="brands">{{cite web |title = Dydrogesterone international brands |url = https://www.drugs.com/international/dydrogesterone.html |publisher = Drugs.com |access-date = 29 November 2020 |url-status = live |archive-url = https://web.archive.org/web/20201129234312/https://www.drugs.com/international/dydrogesterone.html |archive-date = 29 November 2020}}</ref> is a [[progestin]] [[drug|medication]] which is used for a variety of indications, including [[miscarriage|threatened]] or [[recurrent miscarriage]] during [[pregnancy]], [[dysfunctional bleeding]], [[infertility]] due to [[luteal insufficiency]], [[dysmenorrhea]], [[endometriosis]], secondary [[amenorrhea]], [[irregular menstruation|irregular cycles]], [[premenstrual syndrome]], and as a component of [[menopausal hormone therapy]].<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> It is taken [[oral administration|by mouth]].<ref name="pmid16112947" />

<!-- Side effects and mechanism -->

[[Side effect]]s of dydrogesterone include [[menstrual irregularities]], [[headache]], [[nausea]], [[breast tenderness]], and others.<ref name="MishellKirschbaum1990" /><ref name="Femoston-NHS" /> Dydrogesterone is a progestin, or a [[synthetic compound|synthetic]] [[progestogen (medication)|progestogen]], and hence is an [[agonist]] of the [[progesterone receptor]], the [[biological target]] of progestogens like [[progesterone]].<ref name="pmid16112947" /><ref name="Schindler2009">{{cite journal | vauthors = Schindler AE | title = Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium | journal = Maturitas | volume = 65 | issue = Suppl 1 | pages = S3-11 | date = December 2009 | pmid = 19969432 | doi = 10.1016/j.maturitas.2009.10.011 }}</ref> The medication is an atypical progestogen and does not inhibit [[ovulation]].<ref name="pmid16112947" /><ref name="Tausk1972">{{cite journal | vauthors = Tausk MA | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Drugs | journal = International Encyclopaedia of Pharmacology and Therapeutics. | volume = 48 | pages = 19,220,278,285,481 | date = 1972 }}</ref> It has weak [[antimineralocorticoid]] activity and no other important [[hormonal agent|hormonal]] activity.<ref name="pmid16112947" /><ref name="Schindler2009"/>

<!-- History, society, and culture -->

Dydrogesterone was developed in the 1950s and introduced for medical use in 1961.<ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1411|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1411–}}</ref> It is available widely throughout [[Europe]], including in the [[United Kingdom]], and is also marketed in [[Australia]] and elsewhere in the world.<ref name="IndexNominum2000" /><ref name="Publishing2013" /> The medication was previously available in the [[United States]],<ref name="Publishing2013" /> but it has been discontinued in this country.<ref name="Manu2000">{{cite book| vauthors = Manu P |title=The Pharmacotherapy of Common Functional Syndromes: Evidence-Based Guidelines for Primary Care Practice|url=https://books.google.com/books?id=WK3W5WDR5KgC&pg=PA235|date=28 July 2000|publisher=CRC Press|isbn=978-0-7890-0588-5|pages=235–|quote=The drug is not available for clinical use in the United States.}}</ref>

{{TOC limit|3}}

==Medical uses==

Dydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency,<ref name="pmid14667985">{{cite journal | vauthors = Coelingh Bennink HJ, Boerrigter PJ | title = Use of dydrogesterone as a progestogen for oral contraception | journal = Steroids | volume = 68 | issue = 10–13 | pages = 927–9 | date = November 2003 | pmid = 14667985 | doi = 10.1016/j.steroids.2003.07.006 | s2cid = 37470083 }}</ref> [[Infertility]] due to [[luteal insufficiency]]<ref>{{cite journal | vauthors = Balasch J, Vanrell JA, Márquez M, Burzaco I, González-Merlo J | title = Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency | journal = Fertility and Sterility | volume = 37 | issue = 6 | pages = 751–4 | date = June 1982 | pmid = 7084497 | doi = 10.1016/S0015-0282(16)46333-8 | doi-access = }}</ref><ref>{{cite journal |url=https://clinicaltrials.gov/ct2/show/NCT01178931 |title=Dydrogesterone Versus Intravaginal Progesterone in the Luteal Phase Support |journal=[[ClinicalTrials.gov]]|date=27 January 2014 | vauthors = Tomic V }}</ref> including threatened [[miscarriage]],<ref name="pmid20005647">{{cite journal | vauthors = Pandian RU | title = Dydrogesterone in threatened miscarriage: a Malaysian experience | journal = Maturitas | volume = 65 | issue = Suppl 1 | pages = S47-50 | date = December 2009 | pmid = 20005647 | doi = 10.1016/j.maturitas.2009.11.016 }}</ref> habitual or recurrent miscarriage,<ref name=":0">{{cite journal | vauthors = Carp H | title = A systematic review of dydrogesterone for the treatment of recurrent miscarriage | journal = Gynecological Endocrinology | volume = 31 | issue = 6 | pages = 422–30 | date = June 2015 | pmid = 25765519 | doi = 10.3109/09513590.2015.1006618 | s2cid = 20795534 }}</ref> [[Menstruation|Menstrual]] disorders<ref>{{cite journal | vauthors = Tabaste JL, Servaud M, Steiner E, Dabir P, Bene B, Pouzet M | title = [Action of dydrogesterone in postpubertal menstruation disorders] | journal = Revue Française de Gynécologie et d'Obstétrique | volume = 79 | issue = 1 | pages = 19–20, 23–5 | date = January 1984 | pmid = 6531584 }}</ref> premenstrual syndrome,<ref name="ReferenceA">{{cite journal | vauthors = Dennerstein L, Morse C, Gotts G, Brown J, Smith M, Oats J, Burrows G | title = Treatment of premenstrual syndrome. A double-blind trial of dydrogesterone | journal = Journal of Affective Disorders | volume = 11 | issue = 3 | pages = 199–205 | year = 1986 | pmid = 2951407 | doi = 10.1016/0165-0327(86)90070-4 }}</ref> and endometriosis.<ref>{{cite journal | vauthors = Johnston WI | title = Dydrogesterone and endometriosis | journal = British Journal of Obstetrics and Gynaecology | volume = 83 | issue = 1 | pages = 77–80 | date = January 1976 | pmid = 1252380 | doi = 10.1111/j.1471-0528.1976.tb00734.x | s2cid = 72008984 }}</ref> Dydrogesterone has also been registered as a component of [[menopausal hormone therapy]]<ref>{{cite web | url=http://www.nhs.uk/Medicine-Guides/Pages/MedicineOverview.aspx?condition=Hormone%20replacement%20therapy&medicine=Dydrogesterone/Estradiol | title=Dydrogesterone/Estradiol Hormone Replacement Therapy |work=[[National Health Service]]| date=16 August 2018 }}</ref> to counteract the effects of unopposed [[estrogen]] on the endometrium in persons with an intact UTERUS

===Gynecological disorders===

Primary or essential dysmenorrhea is a very common gynecological phenomenon experienced by women during their reproductive years. Clinical studies have shown symptom relief and a reduction in pain with dydrogesterone treatment for dysmenorrhea.<ref name="pmid17943543" /> Secondary amenorrhea is not a specific disease, but is instead a symptom. Dydrogesterone has been found to adequately induce bleeding within a sufficiently estrogen-primed endometrium. When [[estradiol]] levels are found to be low, dydrogesterone treatment is more effective when supplemented with [[estrogen (medication)|estrogen]]s.<ref>{{cite journal | vauthors = Panay N, Pritsch M, Alt J | title = Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study | journal = Gynecological Endocrinology | volume = 23 | issue = 11 | pages = 611–8 | date = November 2007 | pmid = 17891596 | doi = 10.1080/09513590701582554 | s2cid = 25402423 }}</ref>

Endometriosis is a chronic disease which can cause severe, progressive, and at times, incapacitating dysmenorrhea, [[pelvic pain]], [[dyspareunia]] and [[infertility]]. Dydrogesterone relieves pain without inhibiting ovulation, so that patients are able to become pregnant during treatment. Dydrogesterone is particularly suitable in cases where the woman desires to become pregnant and to prevent bleeding problems.<ref name="pmid19945806">{{cite journal | vauthors = Schweppe KW | title = The place of dydrogesterone in the treatment of endometriosis and adenomyosis | journal = Maturitas | volume = 65 | issue = Suppl 1 | pages = S23-7 | date = December 2009 | pmid = 19945806 | doi = 10.1016/j.maturitas.2009.11.011 }}</ref> Dydrogesterone results in statistically significant reductions in the symptoms pelvic pain, dysmenorrhea and dyspareunia after the first treatment cycle for the treatment of post-laparoscopic [[Endometriosis and infertility|endometriosis]].<ref name="pmid17943543">{{cite journal | vauthors = Trivedi P, Selvaraj K, Mahapatra PD, Srivastava S, Malik S | title = Effective post-laparoscopic treatment of endometriosis with dydrogesterone | journal = Gynecological Endocrinology | volume = 23 | issue = Suppl 1 | pages = 73–6 | date = October 2007 | pmid = 17943543 | doi = 10.1080/09513590701669583 | s2cid = 23436064 }}</ref> The amount and duration of menstrual bleeding is also significantly reduced, and from the end of the third month onwards, bleeding was considered normal in the majority of patients. Improvement of endometriosis was observed in 71% of patients.

Dydrogesterone has shown reasonable efficacy in relieving a number of premenstrual syndrome symptoms like [[mood swing]]s and physical symptoms.<ref name="ReferenceA"/> Cyclic treatment with low-dose (10&nbsp;mg/day) dydrogesterone has been found to be effective in the treatment of [[fibrocystic breast changes]] and associated [[mastodynia|breast pain]].<ref name="pmid12227885">{{cite journal | vauthors = Winkler UH, Schindler AE, Brinkmann US, Ebert C, Oberhoff C | title = Cyclic progestin therapy for the management of mastopathy and mastodynia | journal = Gynecological Endocrinology | volume = 15 | issue = Suppl 6 | pages = 37–43 | date = December 2001 | pmid = 12227885 | doi = 10.1080/gye.15.s6.37.43 | s2cid = 27589741 }}</ref>

===Infertility and miscarriage===

Oral dydrogesterone is an effective medication, well tolerated and accepted among patients, and can be considered for routine [[luteal support]]. Advantage of dydrogesterone is oral administration, easy to use and better patient [[compliance (medicine)|compliance]] which results in high satisfaction score of oral dydrogesterone in luteal support of [[In vitro fertilisation|IVF]]/[[Intracytoplasmic sperm injection|ICSI]] cycles.<ref name="pmid25622239">{{cite journal | vauthors = Tomic V, Tomic J, Klaic DZ, Kasum M, Kuna K | title = Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 186 | issue = 1 | pages = 49–53 | date = March 2015 | pmid = 25622239 | doi = 10.1016/j.ejogrb.2014.11.002 }}</ref> Oral administration of progestins dydrogesterone at least similar [[live birth rate]] than vaginal progesterone capsules when used for luteal support in [[embryo transfer]], with no evidence of increased risk of [[miscarriage]].<ref name="BarbosaValadares2018">{{cite journal | vauthors = Barbosa MW, Valadares NP, Barbosa AC, Amaral AS, Iglesias JR, Nastri CO, Martins WP, Nakagawa HM | title = Oral dydrogesterone vs. vaginal progesterone capsules for luteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis | journal = JBRA Assisted Reproduction | volume = 22 | issue = 2 | pages = 148–156 | date = June 2018 | pmid = 29488367 | pmc = 5982562 | doi = 10.5935/1518-0557.20180018 }}</ref><ref name="GriesingerBlockeel2018">{{cite journal | vauthors = Griesinger G, Blockeel C, Sukhikh GT, Patki A, Dhorepatil B, Yang DZ, Chen ZJ, Kahler E, Pexman-Fieth C, Tournaye H | title = Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial | journal = Human Reproduction | volume = 33 | issue = 12 | pages = 2212–2221 | date = December 2018 | pmid = 30304457 | doi = 10.1093/humrep/dey306 | pmc = 6238366 | doi-access = free }}</ref>

Threatened [[miscarriage]] is defined as bleeding during the first 20 weeks of pregnancy while the cervix is closed. It is the most common complication in pregnancy, occurring in 20% of all pregnancies. [[Recurrent miscarriage|Recurrent abortion]] is defined as the loss of three or more consecutive pregnancies. Dydrogesterone is associated with approximately two-fold significant reduction in the miscarriage rate as compared to standard care in threatened and recurrent miscarriages with minimal side effects.<ref name=":0" /><ref name="pmid22794306">{{cite journal | vauthors = Carp H | title = A systematic review of dydrogesterone for the treatment of threatened miscarriage | journal = Gynecological Endocrinology | volume = 28 | issue = 12 | pages = 983–90 | date = December 2012 | pmid = 22794306 | pmc = 3518297 | doi = 10.3109/09513590.2012.702875 }}</ref>

===Hormone therapy===

The objective behind [[menopausal hormone therapy]] is to actively increase the circulating levels of estrogen to control [[hot flash]]es and to prevent the long-term effects of the [[menopause]], such as [[bone resorption]] and unfavourable changes in [[blood lipids]]. The administration of [[estradiol (medication)|estradiol]] halts, or reverses [[atrophy|atrophic]] changes that occur due to the loss of endogenous estradiol during the menopause.<ref>{{cite journal | vauthors = Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH | title = Postmenopausal hormone therapy: an Endocrine Society scientific statement | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 95 | issue = 7 Suppl 1 | pages = s1–s66 | date = July 2010 | pmid = 20566620 | pmc = 6287288 | doi = 10.1210/jc.2009-2509 }}</ref>

Estrogen promotes endometrial cell growth and in [[Menopause#Postmenopause|postmenopausal]] women with an intact uterus, estrogen [[combination therapy|monotherapy]] results in continued endometrial development without the physiological secretory changes normally brought on by progesterone. This action is associated with an increased incidence of endometrial [[hyperplasia]] and [[carcinoma]]. Additional protection with progestogens is therefore important in patients with an intact uterus who receive estrogen therapy. Dydrogesterone counters the [[cell growth|proliferative]] effect of estrogens on the endometrium and ensures the transition to a secretory pattern and cyclical shedding of the endometrium in serial menopausal hormone therapy regimes. Dydrogesterone effectively protects against the [[ontogeny|ontogenesis]] of endometrial hyperplasia. Unlike androgenic progestogens, dydrogesterone does not reverse the benefits brought on by estradiol on lipid profiles and carbohydrate metabolism. In a continuous, combined menopausal hormone therapy regimen, dydrogesterone retards the proliferation of the endometrium so that it remains atrophic or inactive.<ref>{{cite journal | vauthors = Mueck AO, Seeger H, Bühling KJ | title = Use of dydrogesterone in hormone replacement therapy | journal = Maturitas | volume = 65 | pages = S51-60 | date = December 2009 | issue = Suppl 1 | pmid = 19836909 | doi = 10.1016/j.maturitas.2009.09.013 }}</ref>

===Available forms===

{{See also|Estradiol/dydrogesterone}}

Dydrogesterone is available in the form of 10&nbsp;mg [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s both alone and in combination with [[estradiol (medication)|estradiol]].<ref name="Muller1998">{{cite book| vauthors = Muller A |title=European Drug Index: European Drug Registrations | edition = Fourth |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA407|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=407–}}</ref><ref name="ChyeTeng2014">{{cite book| vauthors = Chye T, Teng TK, Hseon TE |title=Practical Obstetrics And Gynaecology Handbook For O&g Clinicians And General Practitioners|url=https://books.google.com/books?id=1j27CgAAQBAJ&pg=PA704|date=27 May 2014|publisher=World Scientific|isbn=978-981-4522-96-0|pages=704–|edition=2nd}}</ref>

==Contraindications==

{{See also|Progestin#Contraindications}}

==Side effects==

The most commonly reported medication-related adverse reactions in people taking dydrogesterone without an estrogen in clinical trials of indications have included [[menstrual irregularities]], [[headaches]], [[migraine]]s, [[nausea]], [[breast tenderness]], [[bloating]], and [[weight gain]].<ref name="MishellKirschbaum1990">{{cite book| vauthors = Mishell DR, Kirschbaum TH, Morrow CP |title=1990 The Year Book of Obstetrics and Gynecology|date=May 1990|url=https://books.google.com/books?id=0jYWNtrtD8MC|publisher=Year Book Medical|isbn=978-0-8151-6012-0}}</ref><ref name="Femoston-NHS">{{cite web |url=http://www.nhs.uk/Medicine-Guides/Pages/MedicineSideEffects.aspx?condition=Hormone%20replacement%20therapy&medicine=Dydrogesterone/Estradiol |title=Dydrogesterone/Estradiol (Generic Femoston 1/10mg tablets) |work=[[National Health Service (England)]]|date=16 August 2018 }}</ref> The use of progestins, in particular [[medroxyprogesterone acetate]], in treating postmenopausal symptoms have been associated with increased risk of [[Thrombus|blood clots]]<ref>{{cite web |url=http://www.netdoctor.co.uk/womens-health/medicines/femoston.html |title=Femoston |work=NetDoctor.co.uk|date=8 October 2019 }}</ref> and [[breast cancer]] in a study carried out by the [[Women's Health Initiative]]. While the study did not involve dydrogesterone, it is possible, but not certain, that it too increases these risks.<ref>{{cite web |url=https://www.nhlbi.nih.gov/whi/whi_faq.htm |title=Questions and Answers About the WHI Postmenopausal Hormone Therapy Trials |work=[[Women's Health Initiative]]}}</ref>

Dydrogesterone has been [[medical prescription|prescribed]] and used in over 10&nbsp;million pregnancies worldwide. There have been no harmful effects exhibited due to the use of dydrogesterone while pregnant. Dydrogesterone is safe to use during pregnancy only when prescribed and indicated by a [[health professional|medical practitioner]].<ref name="DYDROBOON 10mg Film-Coated Tablets" /> Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose.<ref name="DYDROBOON 10mg Film-Coated Tablets" /> The [[Ames test]] found no evidence of any potential [[mutagen]]ic or toxicity properties.<ref>{{cite web |url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+3321 |title=DYDROGESTERONE |work=[[United States National Library of Medicine]]}}</ref>

{{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}}

==Overdose==

There is not enough clinical data to support [[overdose]] in humans. The maximum dose of dydrogesterone administered to humans to date was 360&nbsp;mg orally, and the medication was found to be well tolerated at this dose.{{Citation needed|date=November 2019}} There are no [[antidote]]s to overdose, and treatment should be based on [[symptom]]s.<ref name="DYDROBOON 10mg Film-Coated Tablets" /> In acute toxicity trials, the LD₅₀ doses in rats were in excess of 4,640&nbsp;mg/kg orally.<ref name="DrugBank">{{cite web |url=http://www.drugbank.ca/drugs/DB00378 |title=Dydrogesterone |work=[[DrugBank]]}}</ref><ref>{{cite journal | vauthors = Reerink EH, Scholer HF, Westerhof P, Querido A, Kassenaar AA, Diczfalusy E, Tillinger KC | title = A new class of hormonally active steroids | journal = Nature | volume = 186 | issue = 4719 | pages = 168–9 | date = April 1960 | pmid = 14436886 | doi = 10.1038/186168a0 | bibcode = 1960Natur.186..168R | s2cid = 4189900 }}</ref>

== Interactions ==

In menopausal hormone therapy, dydrogesterone is administered together with an estrogen. Therefore, the interaction between dydrogesterone and estrogens has been assessed, and no clinically significant interaction has been observed.{{Citation needed|date=November 2019}}

==Pharmacology==

===Pharmacodynamics===

[[File:20α-Dihydrodydrogesterone.svg|thumb|right|225px|[[20α-Dihydrodydrogesterone]] (20α-DHD), the main [[active metabolite|active form]] of dydrogesterone.]]

Dydrogesterone is a highly [[binding selectivity|selective]] [[progestogen (medication)|progestogen]], and due to its unique structure, unlike [[progesterone (medication)|progesterone]] and many other [[progestin]]s, binds almost exclusively to the [[progesterone receptor]] (PR).<ref name="SchindlerCampagnoli2003">{{cite journal | vauthors = Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH | title = Classification and pharmacology of progestins | journal = Maturitas | volume = 46 | issue = Suppl 1 | pages = S7–S16 | date = December 2003 | pmid = 14670641 | doi = 10.1016/j.maturitas.2003.09.014 }}</ref> The [[affinity (pharmacology)|affinity]] of dydrogesterone for the PR is relatively low at about 16% of that of progesterone.<ref name="pmid21376746" /><ref name="CabezaHeuze2014">{{cite journal | vauthors = Cabeza M, Heuze Y, Sánchez A, Garrido M, Bratoeff E | title = Recent advances in structure of progestins and their binding to progesterone receptors | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 30 | issue = 1 | pages = 152–9 | date = February 2015 | pmid = 24666307 | doi = 10.3109/14756366.2014.895719 | s2cid = 10050607 | doi-access = free }}</ref> However, ''[[in vivo]]'', dydrogesterone is comparatively much more potent by the [[oral administration|oral]] [[route of administration|route]], with an equivalent dose, in terms of [[endometrium|endometrial]] [[cell proliferation|proliferation]], that is 10 to 20&nbsp;times lower than that of progesterone.<ref name="ColomboFerraboschi2006">{{cite journal | vauthors = Colombo D, Ferraboschi P, Prestileo P, Toma L | title = A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 98 | issue = 1 | pages = 56–62 | date = January 2006 | pmid = 16216490 | doi = 10.1016/j.jsbmb.2005.07.009 | s2cid = 35936384 }}</ref> This is due to [[pharmacokinetic]] differences between the two medications, namely improved [[bioavailability]] and [[metabolic stability]] with dydrogesterone as well as additional progestogenic activity of its [[metabolite]]s.<ref name="Schindler2009"/> Dydrogesterone binds to and activates both of the major [[isoform]]s of the PR, the [[PR-A]] and [[PR-B]], with a similar selectivity ratio between the two receptors as that of progesterone and with lower [[efficacy]] at the receptors relative to progesterone.<ref name="pmid21376746">{{cite journal | vauthors = Rižner TL, Brožič P, Doucette C, Turek-Etienne T, Müller-Vieira U, Sonneveld E, van der Burg B, Böcker C, Husen B | title = Selectivity and potency of the retroprogesterone dydrogesterone in vitro | journal = Steroids | volume = 76 | issue = 6 | pages = 607–15 | date = May 2011 | pmid = 21376746 | doi = 10.1016/j.steroids.2011.02.043 | s2cid = 31609405 }}</ref> The major [[active metabolite]] of dydrogesterone, [[20α-dihydrodydrogesterone]] (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone.<ref name="pmid21376746" /> As with other progestogens, dydrogesterone has functional [[antiestrogen]]ic effects in certain [[tissue (biology)|tissue]]s, for instance in the [[endometrium]], and induces [[endometrial secretory transformation]].<ref name="pmid16112947" />

Dydrogesterone does not bind importantly to the [[androgen receptor|androgen]], [[estrogen receptor|estrogen]], or [[glucocorticoid receptor]].<ref name="CabezaHeuze2014" /><ref name="pmid21376746" /> As such, it is devoid of [[androgen]]ic or [[antiandrogen]]ic, [[estrogen]]ic or [[antiestrogen]]ic, and [[glucocorticoid]] or [[antiglucocorticoid]] activity.<ref name="SchindlerCampagnoli2003" /><ref name="pmid16112947" /><ref name="pmid21376746" /> Similarly to progesterone however, dydrogesterone binds to the [[mineralocorticoid receptor]] and possesses [[antimineralocorticoid]] activity, but only weakly so.<ref name="pmid16112947" /><ref name="pmid21376746" /> Like other progestins but unlike progesterone, which forms [[sedation|sedative]] [[neurosteroid]] metabolites, dydrogesterone is not able to be metabolized in a similar way, and for this reason, is non-sedative.<ref name="pmid16112947" /> The medication and 20α-DHD do not [[enzyme inhibitor|inhibit]] [[5α-reductase]].<ref name="pmid21376746" /> Dydrogesterone has been found to inhibit [[myometrium]] [[contractility]] via an undefined progesterone receptor-independent mechanism ''[[in vivo]]'' in [[pregnancy|pregnant]] rats and ''[[in vitro]]'' in human [[tissue (biology)|tissue]] at concentrations at which progesterone and other progestogens do not.<ref name="pmid29981319">{{cite journal | vauthors = Yasuda K, Sumi GI, Murata H, Kida N, Kido T, Okada H | title = The steroid hormone dydrogesterone inhibits myometrial contraction independently of the progesterone/progesterone receptor pathway | journal = Life Sciences | volume = 207 | pages = 508–515 | date = August 2018 | pmid = 29981319 | doi = 10.1016/j.lfs.2018.07.004 | s2cid = 51602442 }}</ref>

====Atypical progestogenic profile====

Due to its progestogenic activity, dydrogesterone can produce [[antigonadotropic]] effects at sufficient doses in animals.<ref name="BorisStevenson1966">{{cite journal | vauthors = Boris A, Stevenson RH, Trmal T | title = Some studies of the endocrine properties of dydrogesterone | journal = Steroids | volume = 7 | issue = 1 | pages = 1–10 | date = January 1966 | pmid = 5920860 | doi = 10.1016/0039-128X(66)90131-0 }}</ref> However, it does not suppress secretion of the [[gonadotropin]]s, [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH), or inhibit [[ovulation]] at typical clinical dosages in humans.<ref name="pmid16112947" /><ref name="Tausk1972" /><ref name="Mittal2013">{{cite book| vauthors = Mittal S |title=Threatened Miscarriage – ECAB|url=https://books.google.com/books?id=IF-hYuUy7j0C&pg=PT42|date=12 July 2013|publisher=Elsevier Health Sciences|isbn=978-81-312-3233-0|pages=42–}}</ref> Oral doses of dydrogesterone of 5 to 40&nbsp;mg/day on days 5 to 25 of the cycle fail to suppress ovulation (assessed by [[urine|urinary]] [[pregnanediol]] and [[laparotomy]]), and one study found that ovulation persisted even in women treated with an oral dosage of as great as 400&nbsp;mg/day (assessed by visual inspection of the [[ovary|ovaries]]).<ref name="pmid22078182">{{cite journal | vauthors = Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B | title = Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide | journal = Contraception | volume = 84 | issue = 6 | pages = 549–57 | date = December 2011 | pmid = 22078182 | doi = 10.1016/j.contraception.2011.04.009 }}</ref><ref name="Tausk1972" /> Likewise, an [[intramuscular injection]] of 100&nbsp;mg dydrogesterone in [[microcrystalline]] [[aqueous suspension]] on the first to third day of the cycle did not interfere with the development of an ovulatory pattern of spontaneous uterine contractions in women.<ref name="Tausk1972" /><ref name="EskesHein1970">{{cite journal | vauthors = Eskes TK, Hein PR, Stolte LA, Kars-Villanueva EB, Crone A, Braaksma JT, Janssens J | title = Influence of dydrogesterone on the activity of the nonpregnant human uterus | journal = American Journal of Obstetrics and Gynecology | volume = 106 | issue = 8 | pages = 1235–1241 | date = April 1970 | pmid = 5437816 | doi = 10.1016/0002-9378(70)90524-7 }}</ref> A couple of conflicting studies exist on the issue of ovulation inhibition by dydrogesterone however, with findings of partial or full inhibition of ovulation by oral dydrogesterone.<ref name="Tausk1972" /> This included prevention of the mid-cycle LH and FSH peaks and the luteal-phase rise in [[body temperature]] and pregnanediol [[excretion]].<ref name="Tausk1972" /> Nonetheless, the overall consensus among researchers seems to be that dydrogesterone does not inhibit ovulation in women.<ref name="Tausk1972" /> The apparent inability of dydrogesterone to prevent ovulation is in contrast to all other clinically used progestogens except [[trengestone]], which is closely related to dydrogesterone.<ref name="pmid22078182" /><ref name="HorskyPresl2012" /> Similarly to trengestone but also unlike all other clinically used progestogens, dydrogesterone does not have a [[hyperthermia|hyperthermic]] effect in humans (i.e., it does not increase [[body temperature]]).<ref name="pmid16112947" /><ref name="HorskyPresl2012" /><ref name="pmid679688">{{cite book | vauthors = Taubert HD | title = Female Infertility | chapter = Luteal phase insufficiency | volume = 4 | pages = 78–113 | date = 1978 | pmid = 679688 | doi = 10.1159/000401245| quote = Fig. 17. Lack of hyperthermic effect of retroprogesterone derivative (Trengestone).| series = Contributions to Gynecology and Obstetrics | isbn = 978-3-8055-2791-0 }}</ref>

It has been said that the lack of ovulation inhibition and hyperthermic effect with retroprogesterone derivatives like dydrogesterone may represent a dissociation of peripheral and [[central nervous system|central]] progestogenic activity.<ref name="Henzl1978">{{cite book | vauthors = Henzl MR | chapter = Natural and Synthetic Female Sex Hormones | pages = 421–468 | veditors = Yen SS, Jaffe RB | title = Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management | publisher = W.B. Saunders Co. | year = 1978 | isbn = 978-0-7216-9625-6 }}</ref><ref name="Lauritzen1988">{{cite book | vauthors = Lauritzen C | chapter = Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien | pages = 229–306 | trans-chapter = Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles | veditors = Schneider HP, Lauritzen C, Nieschlag E | title = Grundlagen und Klinik der Menschlichen Fortpflanzung | trans-title = Foundations and Clinic of Human Reproduction | language = de | year = 1988 | publisher = Walter de Gruyter | isbn = 978-3-11-010968-9 | oclc = 35483492 | url = https://books.google.com/books?id=v4HvAQAACAAJ}}</ref> However, a related retroprogesterone derivative, trengestone, likewise does not inhibit ovulation or produce a hyperthermic effect but rather has an [[ovulation stimulant|inducing effect on ovulation]].<ref name="HorskyPresl2012">{{cite book| vauthors = Horsky J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA329|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=329–330}}</ref>

Whereas all other assessed progestins are associated with an increased risk of [[breast cancer]] when combined with an estrogen in postmenopausal women, neither oral progesterone nor dydrogesterone are associated with a significantly increased risk of breast cancer (although the risk of breast cancer is non-significantly higher with dydrogesterone).<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 = Gynecological Endocrinology | volume = 33 | issue = 2 | pages = 87–92 | date = February 2017 | pmid = 27898258 | doi = 10.1080/09513590.2016.1248932 | s2cid = 205631264 }}</ref><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 | url = http://www.repository.heartofengland.nhs.uk/278/1/Are%20progestins%20really%20necessary%20as%20part%20of%20a%20combined%20HRT%20regime.docx.pdf | access-date = 2019-09-18 | archive-date = 2017-08-11 | archive-url = https://web.archive.org/web/20170811050423/http://www.repository.heartofengland.nhs.uk/278/1/Are%20progestins%20really%20necessary%20as%20part%20of%20a%20combined%20HRT%20regime.docx.pdf | url-status = dead }}</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> Similarly, like oral progesterone but in contrast to other progestins, dydrogesterone does not appear to further increase the risk of [[venous thromboembolism]] when used in combination with an oral estrogen.<ref name="pmid23835005">{{cite journal | vauthors = Stevenson JC, Panay N, Pexman-Fieth C | title = Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety | journal = Maturitas | volume = 76 | issue = 1 | pages = 10–21 | date = September 2013 | pmid = 23835005 | doi = 10.1016/j.maturitas.2013.05.018 | quote = Dydrogesterone did not increase the risk of VTE associated with oral estrogen (odds ratio (OR) 0.9, 95% CI 0.4–2.3). Other progestogens (OR 3.9, 95% CI 1.5–10.0) were found to further increase the risk of VTE associated with oral estrogen (OR 4.2, 95% CI 1.5–11.6). }}</ref><ref name="pmid19565370">{{cite journal | vauthors = Schneider C, Jick SS, Meier CR | title = Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations | journal = Climacteric | volume = 12 | issue = 5 | pages = 445–53 | date = October 2009 | pmid = 19565370 | doi = 10.1080/13697130902780853 | s2cid = 45890629 | quote = The adjusted relative risk of developing a VTE tended to be lower for E/D users (OR 0.84; 95% CI 0.37–1.92) than for users of other HRT (OR 1.42; 95% CI 1.10–1.82), compared to non-users. }}</ref> Dydrogesterone may also provide inferior [[endometrium|endometrial protection]] relative to other progestins such as [[medroxyprogesterone acetate]] and [[norethisterone acetate]], with a significantly increased risk of [[endometrial cancer]] in combination with an estrogen with long-term therapy (>5&nbsp;years).<ref name="pmid26512775">{{cite journal | vauthors = Prior JC | title = Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence | journal = Current Opinion in Endocrinology, Diabetes and Obesity | volume = 22 | issue = 6 | pages = 495–501 | date = December 2015 | pmid = 26512775 | doi = 10.1097/MED.0000000000000205 | s2cid = 24335817 }}</ref><ref name="SayeghAwwad2017">{{cite book| vauthors = Sayegh R, Awwad JT |title=Essentials of Menopause Management|chapter=Five Decades of Hormone Therapy Research: The Long, the Short, and the Inconclusive|year=2017|pages=13–43|publisher=Springer |doi=10.1007/978-3-319-42451-4_2|isbn=978-3-319-42449-1}}</ref><ref name="pmid19935019">{{cite journal | vauthors = Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O | title = Endometrial cancer in postmenopausal women using estradiol-progestin therapy | journal = Obstetrics and Gynecology | volume = 114 | issue = 6 | pages = 1197–204 | date = December 2009 | pmid = 19935019 | doi = 10.1097/AOG.0b013e3181bea950 | s2cid = 39847270 | doi-access = free }}</ref>

====Other activity====

Dydrogesterone weakly stimulates the [[cell proliferation|proliferation]] of [[MCF-7]] [[breast cancer]] [[cell (biology)|cell]]s ''[[in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the [[progesterone receptor membrane component-1]] (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–13 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | s2cid = 29808177 }}</ref> Certain other progestins are also active in this assay, whereas [[progesterone (medication)|progesterone]] acts neutrally.<ref name="pmid23758160" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as [[medroxyprogesterone acetate]] and [[norethisterone]] in [[clinical trial|clinical studies]].<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 | date = April 2020 | pages = 320–344 | pmid = 31512725 | doi = 10.1210/endrev/bnz001 | pmc = 7156851 | doi-access = free }}</ref>

===Pharmacokinetics===

====Absorption====

Dydrogesterone and its major [[metabolite]], 20α-DHD, have predictable [[pharmacokinetics]]. The single-dose kinetics are linear in the oral dose range of 2.5 to 10&nbsp;mg. The pharmacokinetics do not change during repeated administration of up to 20&nbsp;mg dydrogesterone once daily. Dydrogesterone is readily [[absorption (pharmacokinetics)|absorbed]] with [[oral administration]]. The [[absolute bioavailability]] of dydrogesterone is on average 28%.<ref name="Femoston-Label">{{cite web | url=http://www.medicines.ie/printfriendlydocument.aspx?documentid=5165&companyid=3070 | title=Femoston 2/10mg film-coated tablets | work=medicines.ie Ireland | access-date=2015-03-16 | archive-date=2015-04-02 | archive-url=https://web.archive.org/web/20150402105544/http://www.medicines.ie/printfriendlydocument.aspx?documentid=5165&companyid=3070 | url-status=dead }}</ref> [[Transport maximum|T_max]] values vary between 0.5 and 2.5&nbsp;hours.<ref name=":2">{{cite web | url=http://www.old.health.gov.il/units/pharmacy/trufot/alonim/dydroboon_dr_1272874913497.pdf | title=Dydroboon Prescribing Information |work=[[Ministry of Health (Israel)]]}}</ref> [[Steady state#Physiology|Steady state]] is attained after 3&nbsp;days of treatment.<ref name="DYDROBOON 10mg Film-Coated Tablets"/> The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5&nbsp;hours post-dose.<ref name="DYDROBOON 10mg Film-Coated Tablets">{{cite web | url=http://www.medicines.ie/medicine/5163/SPC/DYDROBOON+10mg+Film-Coated+Tablets/ | title=DYDROBOON 10mg Film-Coated Tablets | work=medicines.ie Ireland }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

A single [[intramuscular injection]] of 100&nbsp;mg dydrogesterone in [[microcrystalline]] [[aqueous suspension]] has been found to have a [[duration of action]] of 16 to 38&nbsp;days in terms of clinical [[biological effect]] in the [[uterus]] in women.<ref name="Tausk1972" /> This was specifically the time until the onset of [[withdrawal bleeding]] in estrogen-treated amenorrheic women.<ref name="Tausk1972" />

{{Parenteral potencies and durations of progestogens}}

====Distribution====

The [[plasma protein binding]] of dydrogesterone and 20α-DHD are unknown. Based on the plasma protein binding of other progestins however, they are probably bound to [[human serum albumin|albumin]] and not to [[sex hormone-binding globulin]] or [[corticosteroid-binding globulin]].<ref name="FRCOG2015" /><ref name="pmid16112947" />

====Metabolism====

The [[metabolism]] of dydrogesterone occurs in the [[liver]].<ref name="Carp2015">{{cite journal | vauthors = Carp HJ | title = Recurrent Pregnancy Loss. Causes, Controversies, and Treatment. | journal = Second Edition | date = 2015 }}</ref> It is virtually completely metabolized.<ref name="Carp2015" /> The primary metabolic pathway is the [[hydrogenation]] of the 20-[[ketone|keto group]] mainly by [[AKR1C1]] and to a lesser extent [[AKR1C3]], resulting in 20α-DHD. This active metabolite is a progestogen similarly to dydrogesterone, albeit with much lower potency.<ref name="BeraničGobec2011" /> With oral administration of dydrogesterone, circulating levels of 20α-DHD are substantially higher than those of dydrogesterone.<ref name="pmid21376746"/> The ratios of 20α-DHD to dydrogesterone in terms of [[Cmax (pharmacology)|peak]] levels and [[area under the curve (pharmacokinetics)|area-under-the-curve]] (AUC) levels have been found to be 25:1 and 40:1, respectively.<ref name="pmid21376746"/> For these reasons, despite the lower relative progestogenic potency of 20α-DHD, dydrogesterone may act as a [[prodrug]] of this metabolite.<ref name="pmid21376746" />

The metabolism of dydrogesterone differs from progesterone.<ref name="Tausk1972" /> Whereas the major [[metabolite]] of progesterone is [[pregnanediol]], the corresponding derivative of dydrogesterone, retropregnanediol, cannot be detected in [[urine]] with oral administration of dydrogesterone.<ref name="Tausk1972" /> All of the metabolites of dydrogesterone retain the 4,6-diene-3-one structure and are metabolically stable. As such, similarly to progesterone, dydrogesterone does not undergo [[aromatization]].

The mean [[biological half-life|elimination half-lives]] of dydrogesterone and 20α-DHD are in the ranges of 5 to 7&nbsp;hours and 14 to 17&nbsp;hours, respectively.<ref name="BińkowskaWoroń2015" />

====Excretion====

Dydrogesterone and its metabolites are [[excretion|excreted]] predominantly in [[urine]]. Total clearance of plasma is at a rate of 6.4&nbsp;L/min. Within 72&nbsp;hours, excretion is virtually complete. 20α-DHD is preponderantly present in the urine as a conjugate of [[glucuronic acid]]. Approximately 85% of the oral dose is successfully removed from the body within 24&nbsp;hours. Around 90% of excreted material is 20α-DHD.<ref name="Tausk1972" />

====Miscellaneous====

The [[pharmacokinetics]] of dydrogesterone have been reviewed.<ref name="pmid16112947" /><ref name="Springer2013" />

==Chemistry==

{{See also|Retroprogesterone|List of progestogens#Retroprogesterone derivatives}}

[[File:Progesterone and dydrogesterone 3D chemical structures comparison.png|thumb|right|225px|A 3D schematic representation of the chemical structures of progesterone (top) and dydrogesterone (bottom), showing the retrosteroid spatial configuration of dydrogesterone.<ref name="pmid16112947" /><ref name="SchindlerCampagnoli2003" />]]

Dydrogesterone, also known as 6-dehydro-9β,10α-progesterone or as 9β,10α-pregna-4,6-diene-3,20-dione, is a [[synthetic compound|synthetic]] [[pregnane]] [[steroid]] and a [[chemical derivative|derivative]] of [[progesterone (medication)|progesterone]] and [[retroprogesterone]] (9β,10α-progesterone).<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA474|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=474–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA378|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=378–}}</ref> Retroprogesterone derivatives like dydrogesterone are [[structural analog|analogue]]s of progesterone in which the [[hydrogen]] atom at the 9th carbon has been switched from the α-position (below the plane) to the β-position (above the plane) and the [[methyl group]] at the 10th carbon has been switched from the β-position to the α-position.<ref name="HorskyPresl2012" /> This reversed configuration in dydrogesterone results in a "bent" spatial geometry in which the plane of rings A and B is orientated at a 60° angle below the rings C and D.<ref name="pmid16112947" /> Dydrogesterone also has an additional [[double bond]] between the C6 and C7 positions (4,6-dien-3-one configuration).<ref name="Elks2014" /><ref name="IndexNominum2000" /> While its chemical structure is close to that of progesterone, these changes result in dydrogesterone having improved oral activity and metabolic stability, among other differences, in comparison to progesterone.<ref name="pmid16112947" /><ref name="SchindlerCampagnoli2003" />

===Analogues===

Other retroprogesterone derivatives, and analogues of dydrogesterone, include [[trengestone]] (1,6-didehydro-6-chlororetroprogesterone) and [[Ro 6-3129]] (16α-ethylthio-6-dehydroretroprogesterone).<ref name="Elks2014" /><ref name="IndexNominum2000" />

===Synthesis===

Dydrogesterone is synthesized and manufactured by treatment of progesterone with [[ultraviolet|ultraviolet light]] exposure.<ref name="SchindlerCampagnoli2003" />

[[Chemical synthesis|Chemical syntheses]] of dydrogesterone have been published.<ref name="Springer2013">{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA10|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=10–,275–276}}</ref>

==History==

Dydrogesterone is a progestin which was first synthesized by Duphar in the 1950s and was first introduced to the market in 1961. It is unique, being the only retrosteroid that is commercially available and its molecular structure is closely related to that of natural progesterone,<ref name="Schindler2009"/> but it has enhanced oral [[bioavailability]]. It is estimated that during the period from 1977 to 2005<ref>{{cite journal | vauthors = Queisser-Luft A | title = Dydrogesterone use during pregnancy: overview of birth defects reported since 1977 | journal = Early Human Development | volume = 85 | issue = 6 | pages = 375–7 | date = June 2009 | pmid = 19193503 | doi = 10.1016/j.earlhumdev.2008.12.016 }}</ref> around 38 million women were treated with dydrogesterone and that [[fetuses]] were exposed to dydrogesterone ''[[Uterus|in utero]]'' in more than 10 million pregnancies. It has been approved in more than 100 countries worldwide. It is commercially marketed under the brand name Dydroboon and manufactured by [[Mankind Pharma]]. Dydrogesterone was first introduced, by Duphar, as Duphaston in the [[United Kingdom]] in 1961.<ref name="Publishing2013" /> Subsequently, it was introduced in the [[United States]] as Duphaston and Gynorest in 1962 and 1968, respectively.<ref name="Publishing2013" /> Duphaston was removed from the United States market in 1979,<ref name="Freedman1986">{{cite book| vauthors = Freedman W |title=International Products Liability|url=https://books.google.com/books?id=k85WAAAAIAAJ|year=1986|publisher=Kluwer Law Book Publishers|isbn=978-0-930273-10-1|quote=Duphaston was removed from the market in 1979 or about two years after the FDA required the defendant to place warnings on the product.}}</ref> and Gynorest is also no longer available in the United States.<ref name="FDA">{{cite web | title=FDA Approved Drugs|url = https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017388|website=U.S. Food & Drug Administration}}</ref>

==Society and culture==

===Generic names===

''Dydrogesterone'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}, while ''dydrogestérone'' is its {{abbrlink|DCF|Dénomination Commune Française}} and ''didrogesterone'' is its {{abbrlink|DCIT|Denominazione Comune Italiana}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Publishing2013" /><ref name="Drugs.com">[https://www.drugs.com/international/dydrogesterone.html Dydrogesterone – Drugs.com<!-- Bot generated title -->]</ref> It was also originally known as ''isopregnenone''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Publishing2013" /><ref name="Drugs.com" /> Dydrogesterone has also been referred to as ''retroprogesterone'', but should not be confused with [[retroprogesterone]].<ref name="GöretzlehnerLauritzen2012">{{cite book| vauthors = Göretzlehner G, Lauritzen C, Römer T, Rossmanith W |title=Praktische Hormontherapie in der Gynäkologie|url=https://books.google.com/books?id=TIs2WhfYzZ4C&pg=PA148|date=1 January 2012|publisher=Walter de Gruyter|isbn=978-3-11-024568-4|pages=148–}}</ref>

===Brand names===

Dydrogesterone is marketed mainly under the brand names Duphaston (alone) and Femoston (in combination with [[estradiol (medication)|estradiol]]).<ref name="Drugs.com" /><ref name="IndexNominum2000" /> It also is or has been marketed alone under the brand names Dabroston, Divatrone, Dufaston, Duvaron, Dydrofem, Femoston, Gestatron, Gynorest, Prodel, Retrone, Terolut and Zuviston and in combination with estradiol under the brand names Climaston, Femaston, and Femphascyl.<ref name="brands" /><ref name="IndexNominum2000" /><ref name="Elks2014" /><ref name="Publishing2013" />

===Availability===

Dydrogesterone is available widely throughout the world.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> It is marketed in the [[United Kingdom]], [[India]], [[Ireland]], [[South Africa]], and [[Australia]], but not in the [[United States]], [[Canada]], or [[New Zealand]].<ref name="Drugs.com" /><ref name="IndexNominum2000" /> The medication was previously available in the United States,<ref name="Publishing2013" /> but has since been discontinued in this country.<ref name="Manu2000" /> Dydrogesterone is also available in elsewhere in [[Europe]], as well as in [[Central America|Central]] and [[South America]], [[Asia]], and [[North Africa]].<ref name="Drugs.com" /><ref name="IndexNominum2000" />

== References ==

* [[Estradiol/dydrogesterone]]

== References ==

{{Reflist}}

== Further reading ==

{{refbegin|30em}}

* {{cite journal | vauthors = Foster RH, Balfour JA | title = Estradiol and dydrogesterone. A review of their combined use as hormone replacement therapy in postmenopausal women | journal = Drugs & Aging | volume = 11 | issue = 4 | pages = 309–32 | date = October 1997 | pmid = 9342560 | doi = 10.2165/00002512-199711040-00006 | s2cid = 1733575 }}

* {{cite journal | vauthors = Gruber CJ, Huber JC | title = The role of dydrogesterone in recurrent (habitual) abortion | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 97 | issue = 5 | pages = 426–30 | date = December 2005 | pmid = 16188436 | doi = 10.1016/j.jsbmb.2005.08.009 | s2cid = 25237037 }}

* {{cite journal | vauthors = Seeger H, Mueck AO | title = Effects of dydrogesterone on the vascular system | journal = Gynecological Endocrinology | volume = 23 | issue = Suppl 1 | pages = 2–8 | date = October 2007 | pmid = 17943533 | doi = 10.1080/09513590701584998 | s2cid = 13380251 }}

* {{cite journal | vauthors = Simoncini T, Mannella P, Pluchino N, Genazzani AR | title = Comparative effects of dydrogesterone and medroxyprogesterone acetate in critical areas: the brain and the vessels | journal = Gynecological Endocrinology | volume = 23 | issue = Suppl 1 | pages = 9–16 | date = October 2007 | pmid = 17943534 | doi = 10.1080/09513590701585094 | s2cid = 21885370 }}

* {{cite journal | vauthors = Queisser-Luft A | title = Dydrogesterone use during pregnancy: overview of birth defects reported since 1977 | journal = Early Human Development | volume = 85 | issue = 6 | pages = 375–7 | date = June 2009 | pmid = 19193503 | doi = 10.1016/j.earlhumdev.2008.12.016 }}

* {{cite journal | vauthors = Mueck AO, Seeger H, Bühling KJ | title = Use of dydrogesterone in hormone replacement therapy | journal = Maturitas | volume = 65 | issue = Suppl 1 | pages = S51-60 | date = December 2009 | pmid = 19836909 | doi = 10.1016/j.maturitas.2009.09.013 }}

* {{cite journal | vauthors = Schindler AE | title = Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium | journal = Maturitas | volume = 65 | issue = Suppl 1 | pages = S3-11 | date = December 2009 | pmid = 19969432 | doi = 10.1016/j.maturitas.2009.10.011 }}

* {{cite journal | vauthors = Schindler AE | title = Dydrogesterone and other progestins in benign breast disease: an overview | journal = Archives of Gynecology and Obstetrics | volume = 283 | issue = 2 | pages = 369–71 | date = February 2011 | pmid = 20383772 | doi = 10.1007/s00404-010-1456-7 | s2cid = 9125889 }}

* {{cite journal | vauthors = Carp H | title = A systematic review of dydrogesterone for the treatment of threatened miscarriage | journal = Gynecological Endocrinology | volume = 28 | issue = 12 | pages = 983–90 | date = December 2012 | pmid = 22794306 | pmc = 3518297 | doi = 10.3109/09513590.2012.702875 }}

* {{cite journal | vauthors = Stevenson JC, Panay N, Pexman-Fieth C | title = Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety | journal = Maturitas | volume = 76 | issue = 1 | pages = 10–21 | date = September 2013 | pmid = 23835005 | doi = 10.1016/j.maturitas.2013.05.018 }}

* {{cite journal | vauthors = Carp H | title = A systematic review of dydrogesterone for the treatment of recurrent miscarriage | journal = Gynecological Endocrinology | volume = 31 | issue = 6 | pages = 422–30 | date = June 2015 | pmid = 25765519 | doi = 10.3109/09513590.2015.1006618 | s2cid = 20795534 }}

* {{cite journal | vauthors = Barbosa MW, Silva LR, Navarro PA, Ferriani RA, Nastri CO, Martins WP | title = Dydrogesterone vs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials | journal = Ultrasound in Obstetrics & Gynecology | volume = 48 | issue = 2 | pages = 161–70 | date = August 2016 | pmid = 26577241 | doi = 10.1002/uog.15814 | doi-access = free }}

* {{cite journal | vauthors = Mirza FG, Patki A, Pexman-Fieth C | title = Dydrogesterone use in early pregnancy | journal = Gynecological Endocrinology | volume = 32 | issue = 2 | pages = 97–106 | date = 2016 | pmid = 26800266 | doi = 10.3109/09513590.2015.1121982 | s2cid = 21807283 }}

* {{cite journal | vauthors = Hudic I, Schindler AE, Szekeres-Bartho J, Stray-Pedersen B | title = Dydrogesterone and pre-term birth | journal = Hormone Molecular Biology and Clinical Investigation | volume = 27 | issue = 3 | pages = 81–3 | date = September 2016 | pmid = 26812800 | doi = 10.1515/hmbci-2015-0064 | s2cid = 43183154 }}

* {{cite journal | vauthors = Raghupathy R, Szekeres-Bartho J | title = Dydrogesterone and the immunology of pregnancy | journal = Hormone Molecular Biology and Clinical Investigation | volume = 27 | issue = 2 | pages = 63–71 | date = August 2016 | pmid = 26812877 | doi = 10.1515/hmbci-2015-0062 | s2cid = 45093373 }}

* {{cite journal | vauthors = Mohamad Razi ZR, Schindler AE | title = Review on role of progestogen (dydrogesterone) in the prevention of gestational hypertension | journal = Hormone Molecular Biology and Clinical Investigation | volume = 27 | issue = 2 | pages = 73–6 | date = August 2016 | pmid = 27101553 | doi = 10.1515/hmbci-2015-0070 | s2cid = 24715919 }}

* {{cite journal | vauthors = Schindler AE | title = Present and future aspects of dydrogesterone in prevention or treatment of pregnancy disorders: an outlook | journal = Hormone Molecular Biology and Clinical Investigation | volume = 27 | issue = 2 | pages = 49–53 | date = August 2016 | pmid = 27662647 | doi = 10.1515/hmbci-2016-0028 | s2cid = 23101112 }}

* {{cite journal | vauthors = Lee HJ, Park TC, Kim JH, Norwitz E, Lee B | title = The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis | journal = BioMed Research International | volume = 2017 | pages = 3616875 | date = 2017 | pmid = 29392134 | pmc = 5748117 | doi = 10.1155/2017/3616875 | doi-access = free }}

* {{cite journal | vauthors = Griesinger G, Blockeel C, Tournaye H | title = Oral dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? | journal = Fertility and Sterility | volume = 109 | issue = 5 | pages = 756–762 | date = May 2018 | pmid = 29778368 | doi = 10.1016/j.fertnstert.2018.03.034 | doi-access = free }}

* {{cite journal | vauthors = Griesinger G, Tournaye H, Macklon N, Petraglia F, Arck P, Blockeel C, van Amsterdam P, Pexman-Fieth C, Fauser BC | title = Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction | journal = Reproductive Biomedicine Online | volume = 38 | issue = 2 | pages = 249–259 | date = February 2019 | pmid = 30595525 | doi = 10.1016/j.rbmo.2018.11.017 | doi-access = free }}

{{refend}}

{{Progestogens and antiprogestogens}}

{{Progesterone receptor modulators}}

{{Mineralocorticoid receptor modulators}}

[[Category:Antimineralocorticoids]]

[[Category:Conjugated dienes]]

[[Category:Diketones]]

[[Category:Drugs developed by AbbVie]]

[[Category:Enones]]

[[Category:Miscarriage]]

[[Category:Pregnanes]]

[[Category:Prodrugs]]

[[Category:Progestogens]]