|Trade names||Duphaston, others|
|Synonyms||Isopregnenone; Dehydroprogesterone; Didrogesteron; 6-Dehydroretroprogesterone; 9β,10α-Pregna-4,6-diene-3,20-dione; NSC-92336|
|AHFS/Drugs.com||International Drug Names|
|Drug class||Progestin; Progestogen|
|Protein binding||? (probably to albumin)|
|Metabolism||Hepatic: AKR1C1, AKR1C3, CYP3A4|
|Metabolites||20α-DHD (exclusively via AKR1C1 and AKRC13)|
|Biological half-life||Parent: 5–7 hours
Metabolite: 14–17 hours
|Chemical and physical data|
|Molar mass||312.446 g/mol|
|3D model (JSmol)|
|Melting point||144 °C (291 °F)|
|Boiling point||463 °C (865 °F)|
|Solubility in water||Insoluble mg/mL (20 °C)|
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. It is taken by mouth.
Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others. Dydrogesterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. The drug is an atypical progestogen and does not inhibit ovulation. It has weak antimineralocorticoid activity and no other important hormonal activity.
Dydrogesterone was developed in the 1950s and introduced for medical use in 1961. It is available widely throughout Europe, including in the United Kingdom, and is also marketed in Australia and elsewhere in the world. The drug was previously available in the United States, but it has been discontinued in this country.
- 1 Medical uses
- 2 Side effects
- 3 Overdose
- 4 Interactions
- 5 Pharmacology
- 6 Chemistry
- 7 History
- 8 Society and culture
- 9 References
Dydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency, Infertility due to luteal insufficiency including threatened miscarriage, habitual or recurrent miscarriage, Menstrual disorders premenstrual syndrome, and endometriosis. Dydrogesterone has also been registered as a component of menopausal hormone therapy to counteract the effects of unopposed estrogen on the endometrium in women with an intact uterus.
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. 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. 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.
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. 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. 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 & physical symptoms. 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.
Infertility and miscarriage
Oral dydrogesterone is effective drug, 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. 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.
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.
The 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.
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.
The most commonly reported drug related adverse reactions of patients treated with dydrogesterone without estrogen treatment in clinical trials of indications include menstrual irregularities, headaches, migraines, nausea, breast tenderness, bloating, and weight gain. The use of progestins, in particular medroxyprogesterone acetate, in treating postmenopausal symptoms have been associated with increased risk of blood clots 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.
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. Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose. The Ames test found no evidence of any potential mutagenic or toxicity properties.
There 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 drug was found to be well-tolerated at this dose. There are no antidotes to overdose and treatment should be based on symptoms. In acute toxicity trials, the LD50 doses in rats were in excess of 4,640 mg/kg orally.
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.
Dydrogesterone 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). The affinity of dydrogesterone for the PR is relatively low at about 16% of that of progesterone. However, in vivo, dydrogesterone is much more potent in comparison, with an equivalent dose, in terms of endometrial proliferation, that is 10 to 20 times lower than that of progesterone. This is due to pharmacokinetic differences between the two drugs, namely improved bioavailability and metabolic stability with dydrogesterone as well as additional progestogenic activity of its metabolites. Dydrogesterone binds to and activates both isoforms of the PR, with a similar selectivity ratio between the two receptors as that of progesterone and lower efficacy at the receptors relative to progesterone. The major active metabolite of dydrogesterone, 20α-dihydrodydrogesterone (20α-DHD), has reduced progestogenic potency relative to dydrogesterone.
Due to its activity as a progestogen, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals. However, it does not suppress gonadotropin secretion or inhibit ovulation at typical clinical dosages in humans; 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). 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. In addition, similarly to trengestone but unlike all other progestogens, dydrogesterone does not increase body temperature (i.e., has no hyperthermic effect). Also, whereas all other assessed progestins are associated with an increased risk of breast cancer when combined with an estrogen in postmenopausal women, neither progesterone nor dydrogesterone are associated with a significantly increased risk. Although dydrogesterone has various atypicalities, the endometrial protection it affords is equivalent to that of other progestins like medroxyprogesterone acetate and norethisterone acetate.
Dydrogesterone does not bind importantly to the androgen, estrogen, and glucocorticoid receptors. As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity. Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so. Unlike progesterone, which forms sedative neurosteroid metabolites, dydrogesterone is not able to be metabolized in a similar way due to structural differences, and for this reason, is non-sedative, similarly to other progestins.
|Dydrogesterone at steroid hormone receptors|
|Ki (nM)||RBA (%)||Ki (nM)||RBA (%)||Ki (nM)||RBA (%)||Ki (nM)|
Effects and properties
When administered orally, dydrogesterone has advantageous pharmacological properties compared to endogenous progesterone: It is orally active at low dosages. It has selective progestogenic properties without any traditional hormonal activity. And the amount absorbed is more predictable than for progesterone, since it is not broken down as easily when passing through the digestive system.
Dydrogesterone is characterized by progestational and PR-mediated antiestrogenic activity. This is demonstrated by its ability to induce a secretory transformation in the endometrium of immature or ovariectomized animals after they have been primed with estrogens (cf. the Clauberg test). The oral progestogenic potency of dydrogesterone is 20 times higher than that of progesterone. The progestational efficacy and potency of dydrogesterone was confirmed by standard test (i.e. delay of menses and induction of withdrawal bleeding). The benefits of estrogen or other target organs are not compromised by dydrogesterone.
At recommended doses, dydrogesterone has no effect on ovulation in healthy women: The biphasic pattern of the basal body temperature is maintained. Normal ovulatory rise in estrogen and pregnanediol. Normal premenstrual biopsy. No modification of vaginal cytology. Cytological evidence of ovulation. And the formation of the corpus luteum has been confirmed by laparotomy. These beneficial results are of particular relevance to the use of dydrogesterone in women who wish to become pregnant.
Unlike many other synthetic progestogens, dydrogesterone is not chemically related to testosterone. Its low affinity for the androgen receptor explains why it has no unwanted androgenic effects even at high doses and after prolonged treatment showed: No virilization (acne, voice changes, hirsutism) of the adult female. No virilizing effects on the genital tract of the female fetus. And no effect on the fertility of the offspring. In addition, dydrogesterone is not converted into estrogen, and has no adverse estrogenic effects on fertility or sexual development.
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 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%. Tmax values vary between 0.5 and 2.5 hours. Steady state is attained after 3 days of treatment. The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose. 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.
Dydrogesterone is virtually completely metabolized, which occurs in the liver. 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. After oral administration, it was found that plasma concentrations of 20α-DHD were substantially heightened than those of the primary drug. The ratios of 20α-DHD and dydrogesterone for AUC and Cmax are in the order of 40 and 25, respectively. As such, dydrogesterone appears to be a prodrug of 20α-DHD. 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. 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.
Dydrogesterone, also known as 6-dehydroretroprogesterone or as 9β,10α-pregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone and retroprogesterone. 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. This results in a "bent" configuration in which the plane of rings A and B is orientated at a 60° angle below the rings C and D. Analogues of dydrogesterone include trengestone (1,6-didehydro-6-chlororetroprogesterone) and Ro 6-3129 (16α-ethylthio-6-dehydroretroprogesterone).
Although its molecular structure is nearly identical to that of natural progesterone, the unique design of dydrogesterone makes it a potent, orally active progestogen. In the dydrogesterone molecule, the hydrogen atom at the 9th carbon is in the β-position and the methyl group at the 10th carbon is in the α-position – a reverse of the progesterone structure, hence the term 'retro' progesterone. Furthermore, it has a second double bond between the 6th carbon and the 7th carbon (the 4,6-dien-3-one configuration). These small differences in chemical structure account for the improved oral activity, metabolic stability, and the lack of estrogenic, androgenic, glucocorticoid, and mineralocorticoid properties of dydrogesterone.
Dydrogesterone is manufactured by treating progesterone with ultraviolet light, leading to a change in the spatial structure. It is produced from the plant steroids, Dioscorea mexicana, a plant of the yam family native to Mexico. Dioscorea contains a sterol called diosgenin. Diosgenin is converted to progesterone.[page needed]
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, but it has enhanced oral bioavailability. It is estimated that during the period from 1977 to 2005 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. Subsequently, it was introduced in the United States as Duphaston and Gynorest in 1962 and 1968, respectively. Duphaston was removed from the United States market in 1979, and Gynorest is also no longer available in the United States.
Society and culture
Dydrogesterone is marketed mainly under the brand names Duphaston (alone) and Femoston (in combination with estradiol). 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.
Dydrogesterone is available widely throughout the world. It is marketed in the United Kingdom, Ireland, South Africa, and Australia, but not in the United States, Canada, or New Zealand. The drug was previously available in the United States, but has since been discontinued in this country. Dydrogesterone is also available in elsewhere in Europe, as well as in Central and South America, Asia, and North Africa.
- J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 474–. ISBN 978-1-4757-2085-3.
- Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 378–. ISBN 978-3-88763-075-1.
- Olbrich, Matthias; Weigl, Kevin; Kahler, Elke; Mihara, Katsuhiro (2016). "Dydrogesterone metabolism in human liver by aldo-keto reductases and cytochrome P450 enzymes". Xenobiotica. 46 (10): 868–874. doi:10.3109/00498254.2015.1134852. ISSN 0049-8254.
- Beranič, N.; Gobec, S.; Rižner, T. Lanišnik (2011). "Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3". Chemico-Biological Interactions. 191 (1–3): 227–233. doi:10.1016/j.cbi.2010.12.012. ISSN 0009-2797. PMID 21182831.
- Howard J.A. Carp, MB, BS, FRCOG (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. pp. 33, 38. ISBN 978-3-319-14385-9.
- Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
- Bińkowska, Małgorzata; Woroń, Jarosław (2015). "Progestogens in menopausal hormone therapy". Menopausal Review. 14 (2): 134–143. doi:10.5114/pm.2015.52154. ISSN 1643-8876. PMC . PMID 26327902.
- Daniel R. Mishell; Thomas H. Kirschbaum; C. Paul Morrow. 1990 The Year Book of Obstetrics and Gynecology. Year Book Medical.
- "Dydrogesterone/Estradiol (Generic Femoston 1/10mg tablets)". National Health Service (England).
- Schindler AE (6 December 2009). "Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium". Maturitas. 65 Suppl 1: S3–11. doi:10.1016/j.maturitas.2009.10.011. PMID 19969432.
- "Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Drugs". International Encyclopaedia of Pharmacology and Therapeutics. 48: 481. 1972.
- William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1411–. ISBN 978-0-8155-1856-3.
- Peter Manu (28 July 2000). The Pharmacotherapy of Common Functional Syndromes: Evidence-Based Guidelines for Primary Care Practice. CRC Press. pp. 235–. ISBN 978-0-7890-0588-5.
The drug is not available for clinical use in the United States.
- Coelingh Bennink HJ; Boerrigter PJ. (2003). "Use of dydrogesterone as a progestogen for oral contraception". Steroids. 68: 927–9. doi:10.1016/j.steroids.2003.07.006. PMID 14667985.
- Balasch J; Vanrell JA; Márquez M; Burzaco I; González-Merlo J. (June 1982). "Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency". Fertil Steril. 37: 751–4. PMID 7084497.
- "Dydrogesterone Versus Intravaginal Progesterone in the Luteal Phase Support". ClinicalTrials.gov.
- Pandian RU (2009). "Dydrogesterone in threatened miscarriage: a Malaysian experience". Maturitas. 65 (1): S47–50. doi:10.1016/j.maturitas.2009.11.016. PMID 20005647.
- Carp H (2015). "A systematic review of dydrogesterone for the treatment of recurrent miscarriage". Gynecol Endocrinol. 31: 1–9. doi:10.3109/09513590.2015.1006618. PMID 25765519.
- Tabaste JL; Servaud M; Steiner E; Dabir P; Bene B; Pouzet M. (1984). "Action of dydrogesterone in postpubertal menstruation disorders". Rev Fr Gynecol Obstet. 79: 19–20, 23–5. PMID 6531584.
- Dennerstein L; Morse C; Gotts G; Brown J; Smith M; Oats J; Burrows G. (1986). "Treatment of premenstrual syndrome. A double-blind trial of dydrogesterone". J Affect Disord. 11: 199–205. doi:10.1016/0165-0327(86)90070-4. PMID 2951407.
- Johnston WI. (1976). "Dydrogesterone and endometriosis". Br J Obstet Gynaecol. 83: 77–80. doi:10.1111/j.1471-0528.1976.tb00734.x. PMID 1252380.
- "Dydrogesterone/Estradiol Hormone Replacement Therapy". National Health Service.
- Trivedi P; Selvaraj K; Mahapatra PD; Srivastava S; Malik S. (2007). "Effective post-laparoscopic treatment of endometriosis with dydrogesterone". Gynecol Endocrinol. 23 (Suppl 1): 73–6. doi:10.1080/09513590701669583. PMID 17943543.
- Panay N; Pritsch M; Alt J. (2007). "Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study". Gynecol Endocrinol. 23: 611–8. doi:10.1080/09513590701582554. PMID 17891596.
- "A Comparative Study between Norethisterone Progestogens and Dydrogesterone in the Treatment of Dysfunctional Uterine Bleeding" (PDF). Science Publications.
- Schweppe KW. (2009). "The place of dydrogesterone in the treatment of endometriosis and adenomyosis". Maturitas. 65 (Suppl 1): S23–7. doi:10.1016/j.maturitas.2009.11.011. PMID 19945806.
- Winkler UH, Schindler AE, Brinkmann US, Ebert C, Oberhoff C (2001). "Cyclic progestin therapy for the management of mastopathy and mastodynia". Gynecol. Endocrinol. 15 Suppl 6: 37–43. doi:10.1080/gye.15.s6.37.43. PMID 12227885.
- Tomic V, Tomic J, Klaic DZ, Kasum M, Kuna K (2014). "Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial". Eur J Obstet Gynecol Reprod Biol. 186 (1): 49–53. doi:10.1016/j.ejogrb.2014.11.002. PMID 25622239.
- Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–71. ISBN 0-07-142280-3.
- Carp H (2012). "A systematic review of dydrogesterone for the treatment of threatened miscarriage". Gynecol Endocrinol. 28 (12): 983–90. doi:10.3109/09513590.2012.702875. PMC . PMID 22794306.
- "Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement". The Journal of Clinical Endocrinology and Metabolism.
- Mueck AO; Seeger H; Bühling KJ. (2009). "Use of dydrogesterone in hormone replacement therapy". Maturitas. 65 Suppl 1: S51–60. doi:10.1016/j.maturitas.2009.09.013. PMID 19836909.
- Muller (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 407–. ISBN 978-3-7692-2114-5.
- Tan Thiam Chye; Tan Kim Teng; Tay Eng Hseon (27 May 2014). Practical Obstetrics And Gynaecology Handbook For O&g Clinicians And General Practitioners (2nd Edition). World Scientific. pp. 704–. ISBN 978-981-4522-96-0.
- "Femoston". NetDoctor.co.uk.
- "Questions and Answers About the WHI Postmenopausal Hormone Therapy Trials". Women's Health Initiative.
- "Duphaston 10mg Film-Coated Tablets". medicines.ie Ireland.
- "DYDROGESTERONE". United States National Library of Medicine.
- "Dydrogesterone". DrugBank.
- Reerink EH, Schöler HFL, Westerhof P; et al. (1960). "A new class of hormonally active steroids". Nature. 186: 168–186. doi:10.1038/186168a0.
- Schindler, Adolf E; Campagnoli, Carlo; Druckmann, René; Huber, Johannes; Pasqualini, Jorge R; Schweppe, Karl W; Thijssen, Jos H.H (2003). "Classification and pharmacology of progestins". Maturitas. 46: 7–16. doi:10.1016/j.maturitas.2003.09.014. ISSN 0378-5122. PMID 14670641.
- Rižner TL, Brožič P, Doucette C, Turek-Etienne T, Müller-Vieira U, Sonneveld E, van der Burg B, Böcker C, Husen B (May 2011). "Selectivity and potency of the retroprogesterone dydrogesterone in vitro". Steroids. 76 (6): 607–15. doi:10.1016/j.steroids.2011.02.043. PMID 21376746.
- Cabeza, Marisa; Heuze, Yvonne; Sánchez, Araceli; Garrido, Mariana; Bratoeff, Eugene (2014). "Recent advances in structure of progestins and their binding to progesterone receptors". Journal of Enzyme Inhibition and Medicinal Chemistry. 30 (1): 152–159. doi:10.3109/14756366.2014.895719. ISSN 1475-6366.
- Colombo, Diego; Ferraboschi, Patrizia; Prestileo, Paolo; Toma, Lucio (2006). "A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy". The Journal of Steroid Biochemistry and Molecular Biology. 98 (1): 56–62. doi:10.1016/j.jsbmb.2005.07.009. ISSN 0960-0760. PMID 16216490.
- Schindler, Adolf E. (2009). "Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium". Maturitas. 65: S3–S11. doi:10.1016/j.maturitas.2009.10.011. ISSN 0378-5122. PMID 19969432.
- Boris, Alfred; Stevenson, Richard H.; Trmal, Thelma (1966). "Some studies of the endocrine properties of dydrogesterone". Steroids. 7 (1): 1–10. doi:10.1016/0039-128X(66)90131-0. ISSN 0039-128X.
- Suneeta Mittal (12 July 2013). Threatened Miscarriage - ECAB. Elsevier Health Sciences. pp. 42–. ISBN 81-312-3233-6.
- Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B (2011). "Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide". Contraception. 84 (6): 549–57. doi:10.1016/j.contraception.2011.04.009. PMID 22078182.
- J. Horsky; J. Presl (6 December 2012). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 329–. ISBN 978-94-009-8195-9.
- Taubert HD (1978). "Luteal phase insufficiency". Contrib Gynecol Obstet. 4: 78–113. PMID 679688.
Fig. 17. Lack of hyperthermic effect of retroprogesterone derivative (Trengestone).
- Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D (February 2017). "Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis". Gynecol. Endocrinol. 33 (2): 87–92. doi:10.1080/09513590.2016.1248932. PMID 27898258.
- Sturdee DW (2013). "Are progestins really necessary as part of a combined HRT regimen?". Climacteric. 16 Suppl 1: 79–84. doi:10.3109/13697137.2013.803311. PMID 23651281.
- Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O (December 2009). "Endometrial cancer in postmenopausal women using estradiol-progestin therapy". Obstet Gynecol. 114 (6): 1197–204. doi:10.1097/AOG.0b013e3181bea950. PMID 19935019.
- "Classification and pharmacology of progestins". Maturitas.
- "Severity of Bleeding as a Predictor of Quality of Life (QoL) in Women With Heavy Menstrual Bleeding (HMB) Under Dydrogesterone Treatment". ClinicalTrials.gov.
- "Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study". ResearchGate.
- "Femoston 2/10mg film-coated tablets". medicines.ie Ireland.
- "Duphaston Prescribing Information" (PDF). Ministry of Health (Israel).
- "Recurrent Pregnancy Loss. Causes, Controversies, and Treatment". Second Edition. 2015.
- "Dydrogesterone (Duphaston®) and its 20-Dihydro-derivative as Selective Estrogen Enzyme Modulators in Human Breast Cancer Cell Lines. Effect on Sulfatase and on 17‚-Hydroxysteroid Dehydrogenase (17‚-HSD) Activity" (PDF). Anticancer Research.
- "Use of Dydrogesterone as a progestogen for oral contraception". DeepDyveScienceDirect.
- Recurrent Pregnancy Loss. Causes, Controversies, and Treatment. 2nd Edition. CRC Press. 2014. ISBN 9781482216141.
- Schindler, AE (Dec 2009). "Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium". Maturitas. 65 Suppl 1: S3–11. doi:10.1016/j.maturitas.2009.10.011. PMID 19969432.
- Queisser-Luft A (3 February 2009). "Dydrogesterone use during pregnancy: overview of birth defects reported since 1977". Early Hum Dev. 85: 375–7. doi:10.1016/j.earlhumdev.2008.12.016. PMID 19193503.
- Warren Freedman (1986). International Products Liability. Kluwer Law Book Publishers. ISBN 978-0-930273-10-1.
Duphaston was removed from the market in 1979 or about two years after the FDA required the defendant to place warnings on the product.
- "FDA Approved Drugs". U.S. Food & Drug Administration.