Dydrogesterone

Dydrogesterone
Systematic (IUPAC) name
(9β,10α)-pregna-4,6-diene-3,20-dione
Clinical data
AHFS/Drugs.com International Drug Names
Pharmacokinetic data
Bioavailability 28%
Metabolism complete, 20-dihydrodydrogesterone (DHD) metabolite
Biological half-life dydrogesterone (5-7 hours) & DHD (14-17 hours)
Identifiers
CAS Number 152-62-5 YesY
ATC code G03DB01 (WHO)
PubChem CID 9051
DrugBank DB00378 YesY
ChemSpider 8699 YesY
UNII 90I02KLE8K YesY
KEGG D01217 N
ChEBI CHEBI:31527 N
Chemical data
Formula C21H28O2
Molar mass 312.446 g/mol
Physical data
Melting point 144 °C (291 °F)
Boiling point 463 °C (865 °F)
Solubility in water insoluble mg/mL (20 °C)
 NYesY (what is this?)  (verify)

Dydrogesterone (INN, USAN, BAN), is also chemically known as 9β,10α-pregna-4,6-diene-3,20-dione.[1] Dydrogesterone (6-dehydro-retroprogesterone)[2] is a hormonally active, non-androgenic steroid that was developed in the 1950s.

Dydrogesterone has selective progestational activity and does not inhibit ovulation.[3] The greater rigidity of dydrogesterone also positively affects its selectivity,[4] 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.[5] 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.[6]

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.[7] Dydrogesterone has proven effective in the following conditions associated with progesterone deficiency:[8]

Dydrogesterone has also been registered as hormone replacement therapy (HRT) [16] to counter-check the negative effects of unopposed estrogen on the endometrium in women with an intact uterus. Dydrogesterone is relatively safe and well tolerated, and does not exhibit the androgenic side effects that are common with some other progestins, like medroxyprogesterone acetate.[17]

Medical Uses

Menstrual Disorders

Dysmenorrhea

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.[18]

Secondary amenorrhoea

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.[19]

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.[20]

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.[21] According to the Cochrane review 2011,[22] there is clinical evidence in favor of dydrogesterone over micronized progesterone for luteal phase support. Dydrogesterone is used for luteal support in IVF protocols, for treatment of recurrent pregnancy loss.[23]

Miscarriage

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.[12][24]

Endometriosis

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.[25] 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.[26] 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%.

Premenstrual syndrome

Dydrogesterone has shown reasonable efficacy in relieving a number of premenstrual syndrome symptoms like mood swings & physical symptoms.[27]

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.[28]

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.[29]

Pregnancy

Pregnancy

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.[30]

Fertility

Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose.[30]

Over dosage

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 over dosage and subsequent treatments should be based on patient symptoms.[30]

Toxicology

No severe or unforeseen toxicity have been accounted for with the use of dydrogesterone. In acute toxicity trials, the LD50 doses in rats were in excess of 4,640 mg/kg orally.[1]

The Ames test found no evidence of any potential mutagenic or toxicity properties.[31]

Side effects

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,[32] bloating or weight gain.[33]

The use of progestins, in particular medroxyprogesterone acetate, in treating post-menopausal symptoms have been associated with increased risk of blood clots[34] 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.[35]

Chemistry

Dydrogesterone was first synthesised by Duphar in the 1950s. Although its molecular structure is almost identical to that of natural progesterone, its unique design makes it a potent, orally active progestogen.[36] 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.[37]

Pharmacokinetics

Metabolism

Dydrogesterone is readily absorbed after oral administration. Tmax values vary between 0.5 and 2.5 hours.[38] Dydrogesterone is virtually completely metabolised. The primary reaction (metabolic) is the hydrogenation of the 20-keto group, leading to 20-dihydrodydrogesterone (DHD), which is another powerful progestogen. Although metabolized in the liver,[39] the metabolite 20-dihydrodydrogesterone is biologically active, unlike the metabolites of progesterone (pregnanediol, pregnanetriol and pregnanolone) which are inactive. The levels of DHD, which is the main active metabolite, is also found to peak about 1.5 hours post dosing.[30]

After oral administration, it was found that plasma concentrations of dihydrodydrogesterone were substantially heightened than those of the primary drug. The ratios of DHD and Dydrogesterone for AUC and Cmax are in the order of 40 and 25, respectively. Absolute bioavailability is on average 28%.[40] 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 explains its lack of androgenic effects.

Elimination and dependencies

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 average terminal half-lives of DHD and dydrogesterone vary between 14–17 and 5–7 hours, respectively.

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.[30] 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.

Pharmacology

When administered orally Dydrogesterone has advantageous pharmacological properties compared to endogenous progesterone:[41]

Dydrogesterone is characterised by progestational and antiestrogenic activity.[42] 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.[43] 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.[44]

Unlike other synthetic progestogens, dydrogesterone is not chemically related to testosterone.[6] Its low affinity for the androgen receptor explains why it has no unwanted androgenic effects even at high doses and after prolonged treatment showed:

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:

These beneficial results are of particular relevance to the use of dydrogesterone in women who wish to become pregnant.

Dydrogesterone has antigonadotropic properties due to its potent action as a progestin.[45] However, dydrogesterone does not suppress gonadotropin secretion at normal clinical dosages.[46]

History

Dydrogesterone is a steroidal progestin 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,[47] but it has enhanced oral bioavailability.

It is estimated that during the period from 1977 to 2005[48] 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.[7] It is commercially marketed under the brand name Duphaston and manufactured by Abbott (formerly known as Solvay Pharmaceuticals).[6] Dydrogesterone is not available in UK and USA market due to commercial reasons.

Sources

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. Hence, the source is always natural.[49]

See also

References

  1. 1 2 "Dydrogesterone". DrugBank.
  2. ↑ "A new class of hormonally active steroids.". Nature 186: 168–186. 1960. doi:10.1038/186168a0.
  3. ↑ "Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Drugs". International Encyclopaedia of Pharmacology and Therapeutics. 48: 481. 1972.
  4. ↑ 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.
  5. ↑ "Dydrogesterone". Royal Society of Chemistry.
  6. 1 2 3 "What is Duphaston". PrescriptionMedications.in.
  7. 1 2 "Dydrogesterone review". MedicaLook.com.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ "Dydrogesterone Versus Intravaginal Progesterone in the Luteal Phase Support". ClinicalTrials.gov.
  11. ↑ 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.
  12. 1 2 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Johnston WI. (1976). "Dydrogesterone and endometriosis". Br J Obstet Gynaecol 83: 77–80. doi:10.1111/j.1471-0528.1976.tb00734.x. PMID 1252380.
  16. ↑ "Dydrogesterone/Estradiol Hormone Replacement Therapy". National Health Service.
  17. ↑ "Dydrogesterone". MedChemExpress.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ "A Comparative Study between Norethisterone Progestogens and Dydrogesterone in the Treatment of Dysfunctional Uterine Bleeding" (PDF). Science Publications.
  21. ↑ 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.
  22. ↑ van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. (2011). "Luteal phase support for assisted reproduction cycles.". Cochrane Database Syst Rev. 10 (CD009154). doi:10.1002/14651858.CD009154.pub2. PMID 21975790.
  23. ↑ Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–71. ISBN 0-07-142280-3.
  24. ↑ Carp H (2012). "A systematic review of dydrogesterone for the treatment of threatened miscarriage.". Gynecol Endocrinol. 12 (983): 90. doi:10.3109/09513590.2012.702875. PMID 22794306.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ "Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement". The Journal of Clinical Endocrinology and Metabolism.
  29. ↑ 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.
  30. 1 2 3 4 5 "Duphaston 10mg Film-Coated Tablets". medicines.ie Ireland.
  31. ↑ "DYDROGESTERONE". United States National Library of Medicine.
  32. ↑ Daniel R. Mishell; Thomas H. Kirschbaum; C. Paul Morrow. 1990 The Year Book of Obstetrics and Gynecology. Year Book Medical.
  33. ↑ "Dydrogesterone/Estradiol (Generic Femoston 1/10mg tablets)". National Health Service (England).
  34. ↑ "Femoston". NetDoctor.co.uk.
  35. ↑ "Questions and Answers About the WHI Postmenopausal Hormone Therapy Trials". Women's Health Initiative.
  36. ↑ "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.
  37. ↑ "Use of Dydrogesterone as a progestogen for oral contraception". DeepDyveScienceDirect.
  38. ↑ "Duphaston Prescribing Information" (PDF). Ministry of Health (Israel).
  39. ↑ "Recurrent Pregnancy Loss. Causes, Controversies, and Treatment.". Second Edition. 2015.
  40. ↑ "Femoston 2/10mg film-coated tablets". medicines.ie Ireland.
  41. ↑ "Classification and pharmacology of progestins". Maturitas.
  42. ↑ "Severity of Bleeding as a Predictor of Quality of Life (QoL) in Women With Heavy Menstrual Bleeding (HMB) Under Dydrogesterone Treatment". ClinicalTrials.gov.
  43. ↑ "Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.". ResearchGate.
  44. ↑ properties of the progestogen dydrogesterone "Classification and pharmacology of progestins" Check |url= value (help). Maturitas.
  45. ↑ 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.
  46. ↑ Suneeta Mittal (12 July 2013). Threatened Miscarriage - ECAB. Elsevier Health Sciences. pp. 42–. ISBN 81-312-3233-6.
  47. ↑ "Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium.". United States National Library of Medicine, National Institutes of Health.
  48. ↑ 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.
  49. ↑ Recurrent Pregnancy Loss. Causes, Controversies, and Treatment. 2nd Editition. CRC Press. 2014. ISBN 9781482216141.
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