|Trade names||Dabroston, Dufaston, Duphaston, Duvaron, Gestatron, Gynorest, Prodel, Retrone, Terolut|
|Synonyms||Isopregnenone; Dehydroprogesterone; Didrogesteron; 6-Dehydroretroprogesterone; 9β,10α-Pregna-4,6-diene-3,20-dione; NSC-92336|
|AHFS/Drugs.com||International Drug Names|
|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 (INN, USAN, BAN) (brand name Duphaston), also known as isopregnenone or 6-dehydroretroprogesterone, as well as 9β,10α-pregna-4,6-diene-3,20-dione, is a steroidal progestin of the retroprogesterone group that was developed in the 1950s and introduced for clinical use in 1961. It is available widely throughout Europe, including the United Kingdom and many other European countries, and is also marketed in Australia, Hong Kong, and India. The drug was previously marketed in the United States as well, but is now no longer available in this country.
Dydrogesterone has selective progestational activity and does not inhibit ovulation. The greater rigidity of dydrogesterone also positively affects its selectivity, while natural progesterone is less selective, existing in different conformations that more easily bind to different receptors. As a consequence of its better bioavailability and the progestational activity of its main metabolites (20-, 21- and 16-hydroxy derivatives), the equivalent dose of dydrogesterone is 10–20 times lower than that of oral micronized progesterone.
Dydrogesterone is used as an effective, orally active progestogen for gynaecological conditions related to a wide variety of progesterone deficiencies in pregnant women. The molecular structure and pharmacological effects are somewhat similar to endogenous progesterone, although in smaller amounts it is found to be orally active. Its freedom from hormonal effects like those related to corticoid, androgenic, estrogenic, anabolic, and other effects gives dydrogesterone an advantage over other synthesized progestogens.
Dydrogesterone when used therapeutically is closely related to its physiological action on the neuro-endocrine control of ovarian function, as well as on the endometrium. This is an indication in all cases of endogeneous progesterone deficiency - relative or absolute. The molecule was licensed for use in several indications, including threatened or recurrent miscarriage, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhoea, irregular cycles, pre-menstrual syndrome and also as a hormone replacement therapy.
- 1 Medical uses
- 2 Safety
- 3 Side effects
- 4 Interactions
- 5 Pharmacology
- 6 Pharmacokinetics
- 7 Chemistry
- 8 History
- 9 Society and culture
- 10 References
Dydrogesterone has proven effective in the following conditions associated with progesterone deficiency:
- Infertility due to luteal insufficiency
- Threatened miscarriage
- Habitual or recurrent miscarriage.
- Menstrual disorders
- Premenstrual syndrome
Dydrogesterone has also been registered as hormone replacement therapy (HRT) to counter-check the negative effects of unopposed estrogen on the endometrium in women with an intact uterus.
Primary or essential dysmenorrhea is a very common gynaecological 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 amenorrhoea 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.
Dysfunctional uterine bleeding and irregular cycles
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.
Infertility due to luteal insufficiency
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.
Endometriosis is a chronic disease which can cause severe, progressive, and at times, incapacitating dysmenorrhoea, 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%.
Hormone replacement therapy
The objective behind hormone replacement therapy is to actively increase the circulating levels of estrogen to control hot flushes and to prevent the long-term effects of the menopause, such as bone resorption and unfavourable changes in blood lipids. The administration of 17β-oestradiol halts, or reverses atrophic changes that occur due to the loss of endogenous oestradiol 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 replacement 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 HRT regimes. Dydrogesterone effectively protects against the ontogenesis of endometrial hyperplasia. Unlike androgenic progestogens, dydrogesterone does not reverse the benefits brought on by 17β-oestradiol on lipid profiles and carbohydrate metabolism. In a continuous, combined HRT regimen, dydrogesterone retards the proliferation of the endometrium so that it remains atrophic or inactive.
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.
There is not enough clinical data to support overdose in humans. 360 mg is the maximum dose taken to date by humans and dydrogesterone was found to be well-tolerated at that oral dose. Additionally, there are no antidotes to overdose and subsequent treatments should be based on patient symptoms.
The most commonly reported drug related adverse reactions of patients treated with dydrogesterone without estrogen treatment in clinical trials of indications are migraines, headaches, nausea, menstrual disorders and breast pain/tenderness, bloating or weight gain.
The use of progestins, in particular medroxyprogesterone acetate, in treating post-menopausal 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.
In HRT, 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 PR. The affinity of dydrogesterone for the PR is relatively low at 15.9% 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. Although dydrogesterone binds to both isoforms of the PR and has similar activity as an agonist of the PRB as progesterone, its agonistic activity is weak in the case of the PRA. Hence, dydrogesterone shows selectivity for PRB activation. This could confer a therapeutic advantage, as the two receptor isoforms induce different physiological responses in target tissues.
Dydrogesterone does not bind to the androgen receptor, estrogen receptor, or glucocorticoid receptor. As such, it is devoid of androgenic, estrogenic, or glucocorticoid activity. Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so. Due to its activity as a progestogen, dydrogesterone can produce antigonadotropic effects. However, it does not suppress gonadotropin secretion or inhibit ovulation at typical clinical dosages. 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.
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.
- 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 characterised by progestational and PR-mediated antiestrogenic activity. This is demonstrated by its ability to induce a secretory transformation in the endometrium of immature or ovariectomised 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.
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 virilising effects on the genital tract of the female fetus.
- No effect on the fertility of the offspring.
Dydrogesterone is not converted into estrogen, and has no adverse estrogenic effects on fertility or sexual development.
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.
- 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.
Dydrogesterone has predictable pharmacokinetics. The single-dose kinetics are linear in the oral dose range of 2.5–10 mg. The pharmacokinetics do not change during repeated administration of up to 20 mg dydrogesterone once daily. Steady state is attained after 3 days of treatment.
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 readily absorbed after oral administration. Tmax values vary between 0.5 and 2.5 hours. Dydrogesterone is virtually completely metabolized, which occurs in the liver. The primary reaction (metabolic) is the hydrogenation of the 20-keto group mainly by AKR1C1 and to a lesser extent AKR1C3, resulting in 20α-dihydrodydrogesterone (20α-DHD), which is a potent progestogen similarly to dydrogesterone. The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose.
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. Absolute bioavailability is on average 28%.
All the metabolites of dydrogesterone retain the 4,6-diene-3-one structure, and are metabolically stable. As such, dydrogesterone does not undergo aromatisation, which is consistent with its absence of estrogenic effects. Furthermore, dydrogesterone does not undergo 17α-hydroxylation, which may contribute to its lack of androgenic effects.
The average terminal terminal half-lives of DHD and dydrogesterone vary between 14–17 and 5–7 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.
Although its molecular structure is almost identical to that of natural progesterone, its unique design makes it a potent, orally active progestogen. In the dydrogesterone molecule, the hydrogen atom at carbon 9 is in the beta position and the methyl group at carbon 10 is in the alpha position - a reverse of the progesterone structure, hence the term 'retro' progesterone. Furthermore, it has a second double bond between carbon 6 and carbon 7 (the 4, 6-diene-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 ultra-violet 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 steroidal progestin that 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 U.S. market in 1979, and Gynorest is also no longer available in the U.S..
Society and culture
|This section needs expansion. You can help by adding to it. (November 2016)|
- 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.
- William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1411–. ISBN 978-0-8155-1856-3.
- 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. ISSN 0049-8254. doi:10.3109/00498254.2015.1134852.
- 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. ISSN 0009-2797. PMID 21182831. doi:10.1016/j.cbi.2010.12.012.
- 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 (2009). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (sup1): 3–63. ISSN 1369-7137. PMID 16112947. doi:10.1080/13697130500148875.
- Bińkowska, Małgorzata; Woroń, Jarosław (2015). "Progestogens in menopausal hormone therapy". Menopausal Review. 14 (2): 134–143. ISSN 1643-8876. PMC . PMID 26327902. doi:10.5114/pm.2015.52154.
- "Dydrogesterone". DrugBank.
- "A new class of hormonally active steroids.". Nature. 186: 168–186. 1960. doi:10.1038/186168a0.
- 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.
- "Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Drugs". International Encyclopaedia of Pharmacology and Therapeutics. 48: 481. 1972.
- Schindler AE (6 December 2009). "Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium.". Maturitas. 65 Suppl 1: S3–11. PMID 19969432. doi:10.1016/j.maturitas.2009.10.011.
- "Dydrogesterone". Royal Society of Chemistry.
- "What is Duphaston". PrescriptionMedications.in.
- "Dydrogesterone review". MedicaLook.com.
- Coelingh Bennink HJ; Boerrigter PJ. (2003). "Use of dydrogesterone as a progestogen for oral contraception.". Steroids. 68: 927–9. PMID 14667985. doi:10.1016/j.steroids.2003.07.006.
- 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. PMID 20005647. doi:10.1016/j.maturitas.2009.11.016.
- Carp H (2015). "A systematic review of dydrogesterone for the treatment of recurrent miscarriage.". Gynecol Endocrinol. 31: 1–9. PMID 25765519. doi:10.3109/09513590.2015.1006618.
- 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. PMID 2951407.
- Johnston WI. (1976). "Dydrogesterone and endometriosis". Br J Obstet Gynaecol. 83: 77–80. PMID 1252380. doi:10.1111/j.1471-0528.1976.tb00734.x.
- "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. PMID 17943543. doi:10.1080/09513590701669583.
- 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. PMID 17891596. doi:10.1080/09513590701582554.
- "A Comparative Study between Norethisterone Progestogens and Dydrogesterone in the Treatment of Dysfunctional Uterine Bleeding" (PDF). Science Publications.
- 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. PMID 25622239. doi:10.1016/j.ejogrb.2014.11.002.
- 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. PMC . PMID 22794306. doi:10.3109/09513590.2012.702875.
- Schweppe KW. (2009). "The place of dydrogesterone in the treatment of endometriosis and adenomyosis.". Maturitas. 65 (Suppl 1): S23–7. PMID 19945806. doi:10.1016/j.maturitas.2009.11.011.
- "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. PMID 19836909. doi:10.1016/j.maturitas.2009.09.013.
- 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. PMID 12227885. doi:10.1080/gye.15.s6.37.43.
- "Duphaston 10mg Film-Coated Tablets". medicines.ie Ireland.
- "DYDROGESTERONE". United States National Library of Medicine.
- 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).
- "Femoston". NetDoctor.co.uk.
- "Questions and Answers About the WHI Postmenopausal Hormone Therapy Trials". Women's Health Initiative.
- 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. ISSN 0378-5122. PMID 14670641. doi:10.1016/j.maturitas.2003.09.014.
- 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. ISSN 1475-6366. doi:10.3109/14756366.2014.895719.
- 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. ISSN 0960-0760. PMID 16216490. doi:10.1016/j.jsbmb.2005.07.009.
- Schindler, Adolf E. (2009). "Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium". Maturitas. 65: S3–S11. ISSN 0378-5122. PMID 19969432. doi:10.1016/j.maturitas.2009.10.011.
- Boris, Alfred; Stevenson, Richard H.; Trmal, Thelma (1966). "Some studies of the endocrine properties of dydrogesterone". Steroids. 7 (1): 1–10. ISSN 0039-128X. doi:10.1016/0039-128X(66)90131-0.
- Suneeta Mittal (12 July 2013). Threatened Miscarriage - ECAB. Elsevier Health Sciences. pp. 42–. ISBN 81-312-3233-6.
- "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.
- "Duphaston Prescribing Information" (PDF). Ministry of Health (Israel).
- "Recurrent Pregnancy Loss. Causes, Controversies, and Treatment.". Second Edition. 2015.
- "Femoston 2/10mg film-coated tablets". medicines.ie Ireland.
- "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. PMID 19969432. doi:10.1016/j.maturitas.2009.10.011.
- Queisser-Luft A (3 February 2009). "Dydrogesterone use during pregnancy: overview of birth defects reported since 1977.". Early Hum Dev. 85: 375–7. PMID 19193503. doi:10.1016/j.earlhumdev.2008.12.016.
- 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.
- http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=017388&DrugName=GYNOREST&ActiveIngred=DYDROGESTERONE&SponsorApplicant=SOLVAY&ProductMktStatus=3&goto=Search.DrugDetails. Missing or empty