| 词条 | Dydrogesterone |
| 释义 |
| Watchedfields = changed | verifiedrevid = 461091780 | IUPAC_name = (8S,9R,10S,13S,14S,17S)-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 | tradename = Duphaston, others | Drugs.com = {{drugs.com|international|dydrogesterone}} | pregnancy_category = | legal_status = Rx-only | routes_of_administration = By mouth | class = Progestin; Progestogen | bioavailability = 28%[1] | protein_bound = ? (probably to albumin)[1][3] | metabolism = Hepatic: AKR1C1, AKR1C3, CYP3A4[2][3] | metabolites = {{abbrlink|20α-DHD|20α-Dihydrodydrogesterone}} (exclusively via AKR1C1 and AKRC13)[3] | elimination_half-life = {{abbr|Parent|Dydrogesterone}}: 5–7 hours[4] {{abbr|Metabolite|20α-Dihydrodydrogesterone}}: 14–17 hours[4] | excretion = Urine | 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[9][10] | C=21 | H=28 | O=2 | molecular_weight = 312.446 g/mol | 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 | melting_point = 144 | boiling_point = 463 | solubility = Insoluble }}Dydrogesterone, sold under the brand name Duphaston among others, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, and as a component of menopausal hormone therapy.[5] It is taken by mouth.[5]Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others.[13][14] Dydrogesterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[5][6] The medication is an atypical progestogen and does not inhibit ovulation.[5][7] It has weak antimineralocorticoid activity and no other important hormonal activity.[5][6] Dydrogesterone was developed in the 1950s and introduced for medical use in 1961.[8] It is available widely throughout Europe, including in the United Kingdom, and is also marketed in Australia and elsewhere in the world.[10][8] The medication was previously available in the United States,[8] but it has been discontinued in this country.[9] {{TOC limit|3}}Medical usesDydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency,[10] Infertility due to luteal insufficiency[11][12] including threatened miscarriage,[13] habitual or recurrent miscarriage,[14] Menstrual disorders[15] premenstrual syndrome,[16] and endometriosis.[17] Dydrogesterone has also been registered as a component of menopausal hormone therapy[18] to counteract the effects of unopposed estrogen on the endometrium in women with an intact uterus. Gynecological disordersPrimary 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.[35] 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 estrogens.[19] Apart from a wide variety of medications in use to reduce heavy menstrual bleeding in patients with ovulatory cycles, oral progestogens like dydrogesterone have been found to be the most commonly prescribed as it has been found to prevent heavy bleeding.[20] 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.[21] 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.[22] 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 and cure in 21%. Dydrogesterone has shown reasonable efficacy in relieving a number of premenstrual syndrome symptoms like mood swings and physical symptoms.[16] Cyclic treatment with low-dose (10 mg/day) dydrogesterone has been found to be effective in the treatment of fibrocystic breast changes and associated breast pain.[23] Infertility and miscarriageOral 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 which results in high satisfaction score of oral dydrogesterone in luteal support of IVF/ICSI cycles.[24] According to the latest Cochrane review (2015), no evidence showed a difference between synthetic and micronized progesterone for luteal phase support in terms of successful pregnancies. Dydrogesterone is used for luteal support in IVF protocols, for treatment of recurrent pregnancy loss.[25] 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 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.[14][26] Hormone therapyThe objective behind menopausal hormone therapy is to actively increase the circulating levels of estrogen to control hot flashes and to prevent the long-term effects of the menopause, such as bone resorption and unfavourable changes in blood lipids. The administration of estradiol halts, or reverses atrophic changes that occur due to the loss of endogenous estradiol during the menopause.[27] Estrogen promotes endometrial cell growth and in postmenopausal women with an intact uterus, estrogen 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 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 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.[28] Available formsDydrogesterone is available in the form of 10 mg oral tablets both alone and in combination with estradiol.[29][30] Contraindications{{See also|Progestin#Contraindications}}Side effectsThe most commonly reported medication-related adverse reactions in people taking dydrogesterone without an estrogen in clinical trials of indications have included menstrual irregularities, headaches, migraines, nausea, breast tenderness, bloating, and weight gain.[31][32] The use of progestins, in particular medroxyprogesterone acetate, in treating postmenopausal symptoms have been associated with increased risk of blood clots[33] 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.[34] Dydrogesterone has been prescribed and used in over 10 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 medical practitioner.[54] Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose.[54] The Ames test found no evidence of any potential mutagenic or toxicity properties.[35] OverdoseThere is not enough clinical data to support overdose in humans. The maximum dose of dydrogesterone administered to humans to date was 360 mg orally and the medication was found to be well-tolerated at this dose. There are no antidotes to overdose and treatment should be based on symptoms.[54] In acute toxicity trials, the LD50 doses in rats were in excess of 4,640 mg/kg orally.[36][37] InteractionsIn 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. PharmacologyPharmacodynamicsDydrogesterone is a highly selective progestogen, and due to its unique structure, unlike progesterone and many other progestins, binds almost exclusively to the progesterone receptor (PR).[38] The affinity of dydrogesterone for the PR is relatively low at about 16% of that of progesterone.[61][39] However, in vivo, dydrogesterone is much more potent in comparison via the oral route, with an equivalent dose, in terms of endometrial proliferation, that is 10 to 20 times lower than that of progesterone.[40] 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 metabolites.[41] Dydrogesterone binds to and activates both of the major isoforms 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.[42] The major active metabolite of dydrogesterone, 20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone.[42] As with other progestogens, dydrogesterone has functional antiestrogenic effects in certain tissues, for instance in the endometrium, and induces endometrial secretory transformation.[5] Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals.[43] However, it does not suppress gonadotropin secretion or inhibit ovulation at typical clinical dosages in humans;[5][44] dosages of dydrogesterone of 5 to 40 mg/day fail to suppress ovulation (as assessed by urinary pregnanediol and laparotomy), and one study found that ovulation persisted even in women treated with a dosage as high as 400 mg/day (assessed by visual inspection of the ovaries).[45] The inability of dydrogesterone to prevent ovulation in humans is in contrast to all other marketed progestogens except trengestone, which is closely related to dydrogesterone structurally.[45][46] In addition, similarly to trengestone but unlike all other progestogens, dydrogesterone does not increase body temperature (i.e., it has no hyperthermic effect).[5][46][47] Also, 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 increased with dydrogesterone).[48][49][50] 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.[51][52] However, as with oral progesterone, dydrogesterone offers inferior endometrial protection relative to other progestogens 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 years).[53][54][55] Dydrogesterone does not bind importantly to the androgen, estrogen, or glucocorticoid receptor.[39][42] As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity.[38][5][42] Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so.[5][42] Like other progestins but unlike progesterone, which forms sedative neurosteroid metabolites, dydrogesterone is not able to be metabolized in a similar way, and for this reason, is non-sedative.[5] The medication and 20α-DHD do not inhibit 5α-reductase.[42] Dydrogesterone has been found to inhibit myometrium contractility via an undefined progesterone receptor-independent mechanism in vivo in pregnant rats and in vitro in human tissue at concentrations at which progesterone and other progestogens do not.[56] {{Affinities of dydrogesterone and related steroids}}PharmacokineticsDydrogesterone 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 mg. The pharmacokinetics do not change during repeated administration of up to 20 mg dydrogesterone once daily. Dydrogesterone is readily absorbed after oral administration. The absolute bioavailability of dydrogesterone is on average 28%.[57] Tmax values vary between 0.5 and 2.5 hours.[58] Steady state is attained after 3 days of treatment.[54] The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose.[59] The plasma protein binding of dydrogesterone and 20α-DHD are unknown, but based on the plasma protein binding of other progestins, they are probably bound to albumin and not to sex hormone-binding globulin or corticosteroid-binding globulin.[1][5] Dydrogesterone is virtually completely metabolized, which occurs in the liver.[60] The primary metabolic pathway is the hydrogenation of the 20-keto group mainly by AKR1C1 and to a lesser extent AKR1C3, resulting in 20α-DHD, which is a potent progestogen similarly to dydrogesterone, albeit with much lower potency.[3] After oral administration, it was found that plasma concentrations of 20α-DHD were substantially higher than those of dydrogesterone. The ratios of 20α-DHD to dydrogesterone for {{abbrlink|AUC|area under the curve (pharmacokinetics)}} and Cmax are on the order of 40:1 and 25:1, respectively.[42] As such, dydrogesterone appears to be a prodrug of 20α-DHD.[42] All of the metabolites of dydrogesterone retain the 4,6-diene-3-one structure, and are metabolically stable. As such, dydrogesterone does not undergo aromatization, which is consistent with its absence of estrogenic effects. The mean elimination half-lives of DHD and dydrogesterone vary between 14 to 17 hours and 5 to 7 hours, respectively.[4] Dydrogesterone and its metabolites are excreted predominantly in urine. Total clearance of plasma is at a rate of 6.4 L/min. Within 72 hours, excretion is virtually complete. DHD is preponderantly present in the urine as a conjugate of glucuronic acid. Approximately 85% of the oral dose is successfully egested from the body within 24 hours. The pharmacokinetics of dydrogesterone have been reviewed.[5][107] Chemistry{{See also|Retroprogesterone|List of progestogens#Retroprogesterone derivatives}}Dydrogesterone, also known as 6-dehydro-9β,10α-progesterone or as 9β,10α-pregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone and retroprogesterone (9β,10α-progesterone).[61][62] Retroprogesterone derivatives like dydrogesterone are analogues 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.[46] 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.[5] Dydrogesterone also has an additional double bond between the C6 and C7 positions (4,6-dien-3-one configuration).[61][62] While its chemical structure is very close to that of progesterone, these small differences result in dydrogesterone having improved oral activity and metabolic stability, among other differences, in comparison to progesterone.[5][38] AnaloguesOther retroprogesterone derivatives, and analogues of dydrogesterone, include trengestone (1,6-didehydro-6-chlororetroprogesterone) and Ro 6-3129 (16α-ethylthio-6-dehydroretroprogesterone).[61][62] SynthesisDydrogesterone is synthesized and manufactured by treatment of progesterone with ultraviolet light exposure.[38] Chemical syntheses of dydrogesterone have been published.[63]HistoryDydrogesterone 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,[64] but it has enhanced oral bioavailability. It is estimated that during the period from 1977 to 2005[65] around 38 million women were treated with dydrogesterone and that fetuses were exposed to dydrogesterone 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 Duphaston and manufactured by Abbott after it took over Solvay Pharmaceuticals. Dydrogesterone was first introduced, by Duphar, as Duphaston in the United Kingdom in 1961.[8] Subsequently, it was introduced in the United States as Duphaston and Gynorest in 1962 and 1968, respectively.[8] Duphaston was removed from the United States market in 1979,[66] and Gynorest is also no longer available in the United States.[67] Society and cultureGeneric namesDydrogesterone is the 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}}.[61][62][8][68] It was also originally known as isopregnenone.[61][62][8][68] Dydrogesterone has also been referred to as retroprogesterone, but should not be confused with retroprogesterone.[69]Brand namesDydrogesterone is marketed mainly under the brand names Duphaston (alone) and Femoston (in combination with estradiol).[68][62] It also is or has been marketed alone under the brand names Dabroston, Dufaston, Duvaron, Gestatron, Gynorest, Prodel, Retrone, and Terolut and in combination with estradiol under the brand names Climaston, Femaston, and Femphascyl.[68][62][61][8] AvailabilityDydrogesterone is available widely throughout the world.[68][62] It is marketed in the United Kingdom, Ireland, South Africa, and Australia, but not in the United States, Canada, or New Zealand.[68][62] The medication was previously available in the United States,[8] but has since been discontinued in this country.[9] Dydrogesterone is also available in elsewhere in Europe, as well as in Central and South America, Asia, and North Africa.[68][62] References1. ^1 2 {{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}} 2. ^{{cite journal|last1=Olbrich|first1=Matthias|last2=Weigl|first2=Kevin|last3=Kahler|first3=Elke|last4=Mihara|first4=Katsuhiro|title=Dydrogesterone metabolism in human liver by aldo-keto reductases and cytochrome P450 enzymes|journal=Xenobiotica|volume=46|issue=10|year=2016|pages=868–874|issn=0049-8254|doi=10.3109/00498254.2015.1134852|pmid=26796435}} 3. ^1 2 {{cite journal|last1=Beranič|first1=N.|last2=Gobec|first2=S.|last3=Rižner|first3=T. Lanišnik|title=Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3|journal=Chemico-Biological Interactions|volume=191|issue=1–3|year=2011|pages=227–233|issn=0009-2797|doi=10.1016/j.cbi.2010.12.012|pmid=21182831}} 4. ^1 2 {{cite journal|last1=Bińkowska|first1=Małgorzata|last2=Woroń|first2=Jarosław|title=Progestogens in menopausal hormone therapy|journal=Menopausal Review|volume=14|issue=2|year=2015|pages=134–143|issn=1643-8876|doi=10.5114/pm.2015.52154|pmid=26327902|pmc=4498031}} 5. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = }} 6. ^1 {{cite journal|author=Schindler AE|title=Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium.|date=6 December 2009|pmid=19969432|doi=10.1016/j.maturitas.2009.10.011|volume=65 Suppl 1|journal=Maturitas|pages=S3–11}} 7. ^{{cite journal | authorlink = Tausk M.A | 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 = 481 | date = 1972 }} 8. ^1 2 3 4 5 6 7 8 {{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–}} 9. ^1 {{cite book|author=Peter Manu|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.}} 10. ^{{cite journal |author1=Coelingh Bennink HJ |author2=Boerrigter PJ. |title=Use of dydrogesterone as a progestogen for oral contraception. | year=2003 | pmid=14667985 | volume=68 |issue=10–13 | journal=Steroids | pages=927–9 | doi=10.1016/j.steroids.2003.07.006}} 11. ^{{cite journal|author1=Balasch J |author2=Vanrell JA |author3=Márquez M |author4=Burzaco I |author5=González-Merlo J. |title=Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency.|year=June 1982|pmid=7084497|volume=37|issue=6 |journal=Fertil Steril|pages=751–4|doi=10.1016/S0015-0282(16)46333-8 }} 12. ^{{cite web |url=https://clinicaltrials.gov/ct2/show/NCT01178931 |title=Dydrogesterone Versus Intravaginal Progesterone in the Luteal Phase Support |work=ClinicalTrials.gov}} 13. ^{{cite journal | author = Pandian RU | title = Dydrogesterone in threatened miscarriage: a Malaysian experience. | journal = Maturitas | volume = 65 | issue = 1 | pages = S47–50 | year = 2009 | pmid = 20005647 | doi = 10.1016/j.maturitas.2009.11.016 | url = }} 14. ^1 {{cite journal|author=Carp H|title=A systematic review of dydrogesterone for the treatment of recurrent miscarriage.|journal = Gynecol. Endocrinol.|pages = 1–9|year=2015|pmid=25765519|doi=10.3109/09513590.2015.1006618|volume=31|issue=6}} 15. ^{{cite journal |author1=Tabaste JL |author2=Servaud M |author3=Steiner E |author4=Dabir P |author5=Bene B |author6=Pouzet M. |title=Action of dydrogesterone in postpubertal menstruation disorders |year=1984 |pmid=6531584 |volume=79 |issue=1 |journal=Rev Fr Gynecol Obstet |pages=19–20, 23–5}} 16. ^1 {{cite journal |author1=Dennerstein L |author2=Morse C |author3=Gotts G |author4=Brown J |author5=Smith M |author6=Oats J |author7=Burrows G. |title=Treatment of premenstrual syndrome. A double-blind trial of dydrogesterone. |year=1986 |pmid=2951407 |volume=11 |issue=3 |journal=J Affect Disord |pages=199–205 |doi=10.1016/0165-0327(86)90070-4 }} 17. ^{{cite journal |author=Johnston WI. |title=Dydrogesterone and endometriosis |year=1976 |pmid=1252380 |volume=83 |issue=1 |journal=Br J Obstet Gynaecol |pages=77–80 |doi=10.1111/j.1471-0528.1976.tb00734.x}} 18. ^{{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}} 19. ^{{cite journal|author1=Panay N |author2=Pritsch M |author3=Alt J. |title=Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study.|year=2007|pmid=17891596|doi=10.1080/09513590701582554|volume=23|issue=11 |journal=Gynecol Endocrinol|pages=611–8}} 20. ^{{cite web |url=http://thescipub.com/PDF/amjsp.2010.23.26.pdf |title=A Comparative Study between Norethisterone Progestogens and Dydrogesterone in the Treatment of Dysfunctional Uterine Bleeding |work=Science Publications }} 21. ^{{cite journal | author = Schweppe KW.| title = The place of dydrogesterone in the treatment of endometriosis and adenomyosis.| journal = Maturitas| volume = 65| issue = Suppl 1| pages = S23–7| year = 2009 | pmid = 19945806 | doi = 10.1016/j.maturitas.2009.11.011| url = }} 22. ^1 {{cite journal |author1=Trivedi P |author2=Selvaraj K |author3=Mahapatra PD |author4=Srivastava S |author5=Malik S. | title = Effective post-laparoscopic treatment of endometriosis with dydrogesterone.| journal = Gynecol. Endocrinol.| volume = 23| issue = Suppl 1| pages = 73–6| year = 2007 | pmid = 17943543 | doi = 10.1080/09513590701669583| url = }} 23. ^{{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 = Gynecol. 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Endocrinol.| volume = 28| issue = 12| pages = 983–90| year = 2012 | pmid = 22794306 | doi = 10.3109/09513590.2012.702875| pmc=3518297}} 27. ^{{cite journal |title=Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement |journal=The Journal of Clinical Endocrinology and Metabolism |volume=95 |issue=7_supplement_1 |pages=s1–s66 |doi=10.1210/jc.2009-2509 |pmid=20566620 |pmc=6287288 |year = 2010|last1 = Santen|first1 = Richard J.|last2=Allred |first2=D. Craig |last3=Ardoin |first3=Stacy P. |last4=Archer |first4=David F. |last5=Boyd |first5=Norman |last6=Braunstein |first6=Glenn D. |last7=Burger |first7=Henry G. |last8=Colditz |first8=Graham A. |last9=Davis |first9=Susan R. |last10=Gambacciani |first10=Marco |last11=Gower |first11=Barbara A. |last12=Henderson |first12=Victor W. |last13=Jarjour |first13=Wael N. |last14=Karas |first14=Richard H. |last15=Kleerekoper |first15=Michael |last16=Lobo |first16=Roger A. |last17=Manson |first17=Joann E. |last18=Marsden |first18=Jo |last19=Martin |first19=Kathryn A. |last20=Martin |first20=Lisa |last21=Pinkerton |first21=Joann V. |last22=Rubinow |first22=David R. |last23=Teede |first23=Helena |last24=Thiboutot |first24=Diane M. |last25=Utian |first25=Wulf H. }} 28. ^{{cite journal|author1=Mueck AO |author2=Seeger H |author3=Bühling KJ. |title=Use of dydrogesterone in hormone replacement therapy.|year=2009|pmid=19836909|doi=10.1016/j.maturitas.2009.09.013|volume=65 Suppl 1|journal=Maturitas|pages=S51–60}} 29. ^{{cite book|author=Muller|title=European Drug Index: European Drug Registrations, Fourth Edition|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–}} 30. ^{{cite book|author1=Tan Thiam Chye|author2=Tan Kim Teng|author3=Tay Eng Hseon|title=Practical Obstetrics And Gynaecology Handbook For O&g Clinicians And General Practitioners (2nd Edition)|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–}} 31. ^1 {{cite book|author1=Daniel R. 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Paul Morrow|title=1990 The Year Book of Obstetrics and Gynecology|url=https://books.google.com/books?id=0jYWNtrtD8MC|publisher=Year Book Medical}} 32. ^1 {{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)}} 33. ^{{cite web |url=http://www.netdoctor.co.uk/womens-health/medicines/femoston.html |title=Femoston |work=NetDoctor.co.uk}} 34. ^{{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}} 35. ^{{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}} 36. ^{{cite web |url=http://www.drugbank.ca/drugs/DB00378 |title=Dydrogesterone |work=DrugBank}} 37. ^{{cite journal | vauthors = Reerink EH, Schöler HL, Westerhof P, Querido A, Kassenaar AA, Diczfalusy E, Tillinger KC | title = A new class of hormonally active steroids. | journal = Nature | volume = 186 | issue = 4719 | pmid = 14436886 | doi = 10.1038/186168a0 | pages = 168–186 | date = 1960 }} 38. ^1 2 3 4 {{cite journal|last1=Schindler|first1=Adolf E|last2=Campagnoli|first2=Carlo|last3=Druckmann|first3=René|last4=Huber|first4=Johannes|last5=Pasqualini|first5=Jorge R|last6=Schweppe|first6=Karl W|last7=Thijssen|first7=Jos H.H|title=Classification and pharmacology of progestins|journal=Maturitas|volume=46|year=2003|pages=7–16|issn=0378-5122|doi=10.1016/j.maturitas.2003.09.014|pmid=14670641}} 39. ^1 {{cite journal|last1=Cabeza|first1=Marisa|last2=Heuze|first2=Yvonne|last3=Sánchez|first3=Araceli|last4=Garrido|first4=Mariana|last5=Bratoeff|first5=Eugene|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|year=2014|pages=152–159|issn=1475-6366|doi=10.3109/14756366.2014.895719|pmid=24666307}} 40. ^{{cite journal|last1=Colombo|first1=Diego|last2=Ferraboschi|first2=Patrizia|last3=Prestileo|first3=Paolo|last4=Toma|first4=Lucio|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|year=2006|pages=56–62|issn=0960-0760|doi=10.1016/j.jsbmb.2005.07.009|pmid=16216490}} 41. ^{{cite journal|last1=Schindler|first1=Adolf E.|title=Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium|journal=Maturitas|volume=65|year=2009|pages=S3–S11|issn=0378-5122|doi=10.1016/j.maturitas.2009.10.011|pmid=19969432}} 42. ^1 2 3 4 5 6 7 8 {{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 | url = }} 43. ^{{cite journal|last1=Boris|first1=Alfred|last2=Stevenson|first2=Richard H.|last3=Trmal|first3=Thelma|title=Some studies of the endocrine properties of dydrogesterone|journal=Steroids|volume=7|issue=1|year=1966|pages=1–10|issn=0039-128X|doi=10.1016/0039-128X(66)90131-0|pmid=5920860}} 44. ^{{cite book|author=Suneeta Mittal|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–}} 45. ^1 {{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 | year = 2011 | pmid = 22078182 | doi = 10.1016/j.contraception.2011.04.009 | url = }} 46. ^1 2 {{cite book|author1=J. Horsky|author2=J. Presl|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–}} 47. ^{{cite book | vauthors = Taubert HD | title = Luteal phase insufficiency | journal = Contrib Gynecol Obstet | volume = 4 | issue = | pages = 78–113 | date = 1978 | pmid = 679688 | doi = 10.1159/000401245| url = | quote = Fig. 17. Lack of hyperthermic effect of retroprogesterone derivative (Trengestone).| series = Contributions to Gynecology and Obstetrics | isbn = 978-3-8055-2791-0 }} 48. ^{{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 | date = February 2017 | pmid = 27898258 | doi = 10.1080/09513590.2016.1248932 | url = }} 49. ^{{cite journal | vauthors = Sturdee DW | title = Are progestins really necessary as part of a combined HRT regimen? | journal = Climacteric | volume = 16 Suppl 1 | issue = | pages = 79–84 | year = 2013 | pmid = 23651281 | doi = 10.3109/13697137.2013.803311 | url = }} 50. ^{{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 | url = }} 51. ^{{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 | url = | 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).}} 52. ^{{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 | url = | 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.}} 53. ^{{cite journal | vauthors = Prior JC | title = Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence | journal = Curr Opin Endocrinol Diabetes Obes | volume = 22 | issue = 6 | pages = 495–501 | date = December 2015 | pmid = 26512775 | doi = 10.1097/MED.0000000000000205 | url = }} 54. ^{{cite book|last1=Sayegh|first1=Raja|title=Essentials of Menopause Management|last2=Awwad|first2=Johnny T.|chapter=Five Decades of Hormone Therapy Research: The Long, the Short, and the Inconclusive|year=2017|pages=13–43|doi=10.1007/978-3-319-42451-4_2|isbn=978-3-319-42449-1}} 55. ^{{cite journal | vauthors = Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O | title = Endometrial cancer in postmenopausal women using estradiol-progestin therapy | journal = Obstet Gynecol | volume = 114 | issue = 6 | pages = 1197–204 | date = December 2009 | pmid = 19935019 | doi = 10.1097/AOG.0b013e3181bea950 | url = }} 56. ^{{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 Sci. | volume = 207 | issue = | pages = 508–515 | date = August 2018 | pmid = 29981319 | doi = 10.1016/j.lfs.2018.07.004 | url = }} 57. ^{{cite web | url=http://www.medicines.ie/printfriendlydocument.aspx?documentid=5165&companyid=3070 | title=Femoston 2/10mg film-coated tablets |work=medicines.ie Ireland}} 58. ^{{cite web | url=http://www.old.health.gov.il/units/pharmacy/trufot/alonim/duphaston_dr_1272874913497.pdf | title=Duphaston Prescribing Information |work=Ministry of Health (Israel)}} 59. ^1 2 3 4 {{cite web | url=http://www.medicines.ie/medicine/5163/SPC/Duphaston+10mg+Film-Coated+Tablets/ | title=Duphaston 10mg Film-Coated Tablets |work=medicines.ie Ireland}} 60. ^{{cite journal | authorlink = Howard J.A. Carp. | title = Recurrent Pregnancy Loss. Causes, Controversies, and Treatment. | journal = Second Edition | volume = | pages = | date = 2015 }} 61. ^1 2 3 4 5 6 {{cite book|author=J. Elks|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–}} 62. ^1 2 3 4 5 6 7 8 9 10 11 {{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–}} 63. ^1 {{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}} 64. ^{{cite journal |title=Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. | pmid=19969432 | doi=10.1016/j.maturitas.2009.10.011 |volume=65 Suppl 1 |date=Dec 2009 |pages=S3–11 |journal=Maturitas | last1 = Schindler | first1 = AE}} 65. ^{{cite journal|author=Queisser-Luft A|title=Dydrogesterone use during pregnancy: overview of birth defects reported since 1977.|date=3 February 2009|pmid=19193503|doi=10.1016/j.earlhumdev.2008.12.016|volume=85|issue=6|journal=Early Hum Dev|pages=375–7}} 66. ^{{cite book|author=Warren Freedman|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.}} 67. ^{{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}} 68. ^1 2 3 4 5 6 https://www.drugs.com/international/dydrogesterone.html 69. ^{{cite book|author1=Gunther Göretzlehner|author2=Christian Lauritzen|author3=Thomas Römer|author4=Winfried Rossmanith|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–}} Further reading{{Div col|colwidth=30em}}
7 : Antimineralocorticoids|Dienes|Diketones|Miscarriage|Pregnanes|Prodrugs|Progestogens |
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