Dydrogesterone

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Dydrogesterone
Dydrogesterone.svg
Dydrogesterone molecule ball.png
Clinical data
Trade names Duphaston, others [1]
Other namesIsopregnenone; Dehydroprogesterone; Didrogesteron; 6-Dehydroretroprogesterone; 9β,10α-Pregna-4,6-diene-3,20-dione; NSC-92336 [2] [3]
AHFS/Drugs.com International Drug Names
Routes of
administration 		By mouth
Drug class Progestogen; Progestin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 28% [4] [5]
Protein binding ? (probably to albumin) [6] [7]
Metabolism Hepatic: AKR1C1, AKR1C3, CYP3A4 [8] [9]
Metabolites 20α-DHD Tooltip 20α-Dihydrodydrogesterone (exclusively via AKR1C1 and AKRC13) [9]
Elimination half-life Parent: 5–7 hours [10]
Metabolite: 14–17 hours [10]
Excretion Urine
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.280 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H28O2
Molar mass 312.453 g·mol−1
3D model (JSmol)
Melting point 144 °C (291 °F)
Boiling point 463 °C (865 °F)
Solubility in water Insoluble mg/mL (20 °C)
  • 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
  • InChI=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 Yes check.svgY
  • Key:JGMOKGBVKVMRFX-HQZYFCCVSA-N Yes check.svgY
   (verify)

Dydrogesterone, sold under the brand name Duphaston among others, [1] 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. [7] It is taken by mouth. [7]

Contents

Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others. [11] [12] Dydrogesterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [7] [13] The medication is an atypical progestogen and does not inhibit ovulation. [7] [14] It has weak antimineralocorticoid activity and no other important hormonal activity. [7] [13]

Dydrogesterone was developed in the 1950s and introduced for medical use in 1961. [15] It is available widely throughout Europe, including in the United Kingdom, and is also marketed in Australia and elsewhere in the world. [3] [15] The medication was previously available in the United States, [15] but it has been discontinued in that country. [16]

Medical uses

Dydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency, [17] Infertility due to luteal insufficiency [18] [19] including threatened miscarriage, [20] habitual or recurrent miscarriage, [21] Menstrual disorders [22] premenstrual syndrome, [23] and endometriosis. [24] Dydrogesterone has also been registered as a component of menopausal hormone therapy [25] to counteract the effects of unopposed estrogen on the endometrium in persons with an intact UTERUS

Gynecological disorders

Primary or essential dysmenorrhea is a very common gynecological phenomenon experienced by women during their reproductive years. Clinical studies have shown symptom relief and a reduction in pain with dydrogesterone treatment for dysmenorrhea. [26] 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. [27]

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. [28] 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.

Dydrogesterone has shown reasonable efficacy in relieving a number of premenstrual syndrome symptoms like mood swings and physical symptoms. [23] 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. [29]

Infertility and miscarriage

Oral dydrogesterone is an effective medication, well tolerated and accepted among patients, and can be considered for routine luteal support. Advantage of dydrogesterone is oral administration, easy to use and better patient compliance which results in high satisfaction score of oral dydrogesterone in luteal support of IVF/ICSI cycles. [30] Oral administration of progestins dydrogesterone at least similar live birth rate than vaginal progesterone capsules when used for luteal support in embryo transfer, with no evidence of increased risk of miscarriage. [31] [32]

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. [21] [33]

Hormone therapy

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. [34]

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. [35]

Available forms

Dydrogesterone is available in the form of 10 mg oral tablets both alone and in combination with estradiol. [36] [37]

Contraindications

Side effects

The most commonly reported medication-related adverse reactions in people taking dydrogesterone without an estrogen in clinical trials of indications have included menstrual irregularities, headaches, migraines, nausea, breast tenderness, bloating, and weight gain. [11] [12] The use of progestins, in particular medroxyprogesterone acetate, in treating postmenopausal symptoms have been associated with increased risk of blood clots [38] 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. [39]

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. [40] Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose. [40] The Ames test found no evidence of any potential mutagenic or toxicity properties. [41]

Risk of breast cancer with menopausal hormone therapy in large observational studies (Mirkin, 2018)
StudyTherapy Hazard ratio (95% CI Tooltip confidence interval)
E3N-EPIC: Fournier et al. (2005)Estrogen alone1.1 (0.8–1.6)
Estrogen plus progesterone
    Transdermal estrogen
    Oral estrogen		0.9 (0.7–1.2)
0.9 (0.7–1.2)
No events
Estrogen plus progestin
    Transdermal estrogen
    Oral estrogen		1.4 (1.2–1.7)
1.4 (1.2–1.7)
1.5 (1.1–1.9)
E3N-EPIC: Fournier et al. (2008)Oral estrogen alone1.32 (0.76–2.29)
Oral estrogen plus progestogen
     Progesterone
    Dydrogesterone
     Medrogestone
     Chlormadinone acetate
     Cyproterone acetate
     Promegestone
     Nomegestrol acetate
     Norethisterone acetate
     Medroxyprogesterone acetate
Not analyzeda
0.77 (0.36–1.62)
2.74 (1.42–5.29)
2.02 (1.00–4.06)
2.57 (1.81–3.65)
1.62 (0.94–2.82)
1.10 (0.55–2.21)
2.11 (1.56–2.86)
1.48 (1.02–2.16)
Transdermal estrogen alone1.28 (0.98–1.69)
Transdermal estrogen plus progestogen
     Progesterone
    Dydrogesterone
     Medrogestone
     Chlormadinone acetate
     Cyproterone acetate
     Promegestone
     Nomegestrol acetate
     Norethisterone acetate
     Medroxyprogesterone acetate
1.08 (0.89–1.31)
1.18 (0.95–1.48)
2.03 (1.39–2.97)
1.48 (1.05–2.09)
Not analyzeda
1.52 (1.19–1.96)
1.60 (1.28–2.01)
Not analyzeda
Not analyzeda
E3N-EPIC: Fournier et al. (2014)Estrogen alone1.17 (0.99–1.38)
Estrogen plus progesterone or dydrogesterone1.22 (1.11–1.35)
Estrogen plus progestin1.87 (1.71–2.04)
CECILE: Cordina-Duverger et al. (2013)Estrogen alone1.19 (0.69–2.04)
Estrogen plus progestogen
     Progesterone
    Progestins
        Progesterone derivatives
        Testosterone derivatives		1.33 (0.92–1.92)
0.80 (0.44–1.43)
1.72 (1.11–2.65)
1.57 (0.99–2.49)
3.35 (1.07–10.4)
Footnotes:a = Not analyzed, fewer than 5 cases. Sources: See template.
Risk of breast cancer with menopausal hormone therapy by duration in large observational studies (Mirkin, 2018)
StudyTherapy Hazard ratio (95% CI Tooltip confidence interval)
E3N-EPIC: Fournier et al. (2005)aTransdermal estrogen plus progesterone
    <2 years
    2–4 years
    ≥4 years
0.9 (0.6–1.4)
0.7 (0.4–1.2)
1.2 (0.7–2.0)
Transdermal estrogen plus progestin
    <2 years
    2–4 years
    ≥4 years
1.6 (1.3–2.0)
1.4 (1.0–1.8)
1.2 (0.8–1.7)
Oral estrogen plus progestin
    <2 years
    2–4 years
    ≥4 years
1.2 (0.9–1.8)
1.6 (1.1–2.3)
1.9 (1.2–3.2)
E3N-EPIC: Fournier et al. (2008)Estrogen plus progesterone
    <2 years
    2–4 years
    4–6 years
    ≥6 years
0.71 (0.44–1.14)
0.95 (0.67–1.36)
1.26 (0.87–1.82)
1.22 (0.89–1.67)
Estrogen plus dydrogesterone
    <2 years
    2–4 years
    4–6 years
    ≥6 years
0.84 (0.51–1.38)
1.16 (0.79–1.71)
1.28 (0.83–1.99)
1.32 (0.93–1.86)
Estrogen plus other progestogens
    <2 years
    2–4 years
    4–6 years
    ≥6 years
1.36 (1.07–1.72)
1.59 (1.30–1.94)
1.79 (1.44–2.23)
1.95 (1.62–2.35)
E3N-EPIC: Fournier et al. (2014)Estrogens plus progesterone or dydrogesterone
    <5 years
    ≥5 years
1.13 (0.99–1.29)
1.31 (1.15–1.48)
Estrogen plus other progestogens
    <5 years
    ≥5 years
1.70 (1.50–1.91)
2.02 (1.81–2.26)
Footnotes:a = Oral estrogen plus progesterone was not analyzed because there was a low number of women who used this therapy. Sources: See template.

Overdose

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 medication was found to be well tolerated at this dose.[ citation needed ] There are no antidotes to overdose, and treatment should be based on symptoms. [40] In acute toxicity trials, the LD50 doses in rats were in excess of 4,640 mg/kg orally. [42] [43]

Interactions

In menopausal hormone therapy, dydrogesterone is administered together with an estrogen. Therefore, the interaction between dydrogesterone and estrogens has been assessed, and no clinically significant interaction has been observed.[ citation needed ]

Pharmacology

Pharmacodynamics

20a-Dihydrodydrogesterone (20a-DHD), the main active form of dydrogesterone. 20a-Dihydrodydrogesterone.svg
20α-Dihydrodydrogesterone (20α-DHD), the main active form of dydrogesterone.

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). [44] The affinity of dydrogesterone for the PR is relatively low at about 16% of that of progesterone. [45] [46] However, in vivo , dydrogesterone is comparatively much more potent by the oral route, with an equivalent dose, in terms of endometrial proliferation, that is 10 to 20 times lower than that of progesterone. [47] 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. [13] 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. [45] The major active metabolite of dydrogesterone, 20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone. [45] As with other progestogens, dydrogesterone has functional antiestrogenic effects in certain tissues, for instance in the endometrium, and induces endometrial secretory transformation. [7]

Dydrogesterone does not bind importantly to the androgen, estrogen, or glucocorticoid receptor. [46] [45] As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity. [44] [7] [45] Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so. [7] [45] 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. [7] The medication and 20α-DHD do not inhibit 5α-reductase. [45] 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. [48]

Atypical progestogenic profile

Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals. [49] However, it does not suppress secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), or inhibit ovulation at typical clinical dosages in humans. [7] [14] [50] Oral doses of dydrogesterone of 5 to 40 mg/day on days 5 to 25 of the cycle fail to suppress ovulation (assessed by urinary pregnanediol and laparotomy), and one study found that ovulation persisted even in women treated with an oral dosage of as great as 400 mg/day (assessed by visual inspection of the ovaries). [51] [14] Likewise, an intramuscular injection of 100 mg dydrogesterone in microcrystalline aqueous suspension on the first to third day of the cycle did not interfere with the development of an ovulatory pattern of spontaneous uterine contractions in women. [14] [52] A couple of conflicting studies exist on the issue of ovulation inhibition by dydrogesterone however, with findings of partial or full inhibition of ovulation by oral dydrogesterone. [14] This included prevention of the mid-cycle LH and FSH peaks and the luteal-phase rise in body temperature and pregnanediol excretion. [14] Nonetheless, the overall consensus among researchers seems to be that dydrogesterone does not inhibit ovulation in women. [14] The apparent inability of dydrogesterone to prevent ovulation is in contrast to all other clinically used progestogens except trengestone, which is closely related to dydrogesterone. [51] [53] Similarly to trengestone but also unlike all other clinically used progestogens, dydrogesterone does not have a hyperthermic effect in humans (i.e., it does not increase body temperature). [7] [53] [54]

It has been said that the lack of ovulation inhibition and hyperthermic effect with retroprogesterone derivatives like dydrogesterone may represent a dissociation of peripheral and central progestogenic activity. [55] [56] However, a related retroprogesterone derivative, trengestone, likewise does not inhibit ovulation or produce a hyperthermic effect but rather has an inducing effect on ovulation. [53]

Whereas all other assessed progestins are associated with an increased risk of breast cancer when combined with an estrogen in postmenopausal women, neither oral progesterone nor dydrogesterone are associated with a significantly increased risk of breast cancer (although the risk of breast cancer is non-significantly higher with dydrogesterone). [57] [58] [59] 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. [60] [61] Dydrogesterone may also provide inferior endometrial protection relative to other progestins such as medroxyprogesterone acetate and norethisterone acetate, with a significantly increased risk of endometrial cancer in combination with an estrogen with long-term therapy (>5 years). [62] [63] [64]

Other activity

Dydrogesterone weakly stimulates the proliferation of MCF-7 breast cancer cells in vitro , an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). [65] Certain other progestins are also active in this assay, whereas progesterone acts neutrally. [65] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies. [66]

Pharmacokinetics

Absorption

Dydrogesterone and its major metabolite, 20α-DHD, have predictable pharmacokinetics. The single-dose kinetics are linear in the oral dose range of 2.5 to 10 mg. The pharmacokinetics do not change during repeated administration of up to 20 mg dydrogesterone once daily. Dydrogesterone is readily absorbed with oral administration. The absolute bioavailability of dydrogesterone is on average 28%. [4] Tmax values vary between 0.5 and 2.5 hours. [67] Steady state is attained after 3 days of treatment. [40] The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose. [40]

A single intramuscular injection of 100 mg dydrogesterone in microcrystalline aqueous suspension has been found to have a duration of action of 16 to 38 days in terms of clinical biological effect in the uterus in women. [14] This was specifically the time until the onset of withdrawal bleeding in estrogen-treated amenorrheic women. [14]

Parenteral potencies and durations of progestogens [lower-alpha 1] [lower-alpha 2]
CompoundFormDose for specific uses (mg) [lower-alpha 3] DOA [lower-alpha 4]
TFD [lower-alpha 5] POICD [lower-alpha 6] CICD [lower-alpha 7]
Algestone acetophenide Oil soln.-–75–15014–32 d
Gestonorone caproate Oil soln.25–50––8–13 d
Hydroxyprogest. acetate [lower-alpha 8] Aq. susp.350––9–16 d
Hydroxyprogest. caproate Oil soln.250–500 [lower-alpha 9] –250–5005–21 d
Medroxyprog. acetate Aq. susp.50–1001502514–50+ d
Megestrol acetate Aq. susp.-–25>14 d
Norethisterone enanthate Oil soln.100–2002005011–52 d
Progesterone Oil soln.200 [lower-alpha 9] ––2–6 d
Aq. soln. ?––1–2 d
Aq. susp.50–200––7–14 d
Notes and sources:
  1. ↑ Sources: [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86]
  2. ↑ All given by intramuscular or subcutaneous injection.
  3. ↑ Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OID Tooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ↑ Duration of action in days.
  5. ↑ Usually given for 14 days.
  6. ↑ Usually dosed every two to three months.
  7. ↑ Usually dosed once monthly.
  8. ↑ Never marketed or approved by this route.
  9. 1 2 In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Distribution

The plasma protein binding of dydrogesterone and 20α-DHD are unknown. Based on the plasma protein binding of other progestins however, they are probably bound to albumin and not to sex hormone-binding globulin or corticosteroid-binding globulin. [6] [7]

Metabolism

The metabolism of dydrogesterone occurs in the liver. [87] It is virtually completely metabolized. [87] 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. This active metabolite is a progestogen similarly to dydrogesterone, albeit with much lower potency. [9] With oral administration of dydrogesterone, circulating levels of 20α-DHD are substantially higher than those of dydrogesterone. [45] The ratios of 20α-DHD to dydrogesterone in terms of peak levels and area-under-the-curve (AUC) levels have been found to be 25:1 and 40:1, respectively. [45] For these reasons, despite the lower relative progestogenic potency of 20α-DHD, dydrogesterone may act as a prodrug of this metabolite. [45]

The metabolism of dydrogesterone differs from progesterone. [14] Whereas the major metabolite of progesterone is pregnanediol, the corresponding derivative of dydrogesterone, retropregnanediol, cannot be detected in urine with oral administration of dydrogesterone. [14] All of the metabolites of dydrogesterone retain the 4,6-diene-3-one structure and are metabolically stable. As such, similarly to progesterone, dydrogesterone does not undergo aromatization.

The mean elimination half-lives of dydrogesterone and 20α-DHD are in the ranges of 5 to 7 hours and 14 to 17 hours, respectively. [10]

Excretion

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. 20α-DHD is preponderantly present in the urine as a conjugate of glucuronic acid. Approximately 85% of the oral dose is successfully removed from the body within 24 hours. Around 90% of excreted material is 20α-DHD. [14]

Miscellaneous

The pharmacokinetics of dydrogesterone have been reviewed. [7] [88]

Chemistry

A 3D schematic representation of the chemical structures of progesterone (top) and dydrogesterone (bottom), showing the retrosteroid spatial configuration of dydrogesterone. Progesterone and dydrogesterone 3D chemical structures comparison.png
A 3D schematic representation of the chemical structures of progesterone (top) and dydrogesterone (bottom), showing the retrosteroid spatial configuration of dydrogesterone.

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). [2] [3] 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. [53] 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. [7] Dydrogesterone also has an additional double bond between the C6 and C7 positions (4,6-dien-3-one configuration). [2] [3] While its chemical structure is close to that of progesterone, these changes result in dydrogesterone having improved oral activity and metabolic stability, among other differences, in comparison to progesterone. [7] [44]

Analogues

Other retroprogesterone derivatives, and analogues of dydrogesterone, include trengestone (1,6-didehydro-6-chlororetroprogesterone) and Ro 6-3129 (16α-ethylthio-6-dehydroretroprogesterone). [2] [3]

Synthesis

Dydrogesterone is synthesized and manufactured by treatment of progesterone with ultraviolet light exposure. [44]

Chemical syntheses of dydrogesterone have been published. [88]

History

Dydrogesterone is a progestin which was first synthesized by Duphar in the 1950s and was first introduced to the market in 1961. It is unique, being the only retrosteroid that is commercially available and its molecular structure is closely related to that of natural progesterone, [13] but it has enhanced oral bioavailability. It is estimated that during the period from 1977 to 2005 [89] 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 Dydroboon and manufactured by Mankind Pharma. Dydrogesterone was first introduced, by Duphar, as Duphaston in the United Kingdom in 1961. [15] Subsequently, it was introduced in the United States as Duphaston and Gynorest in 1962 and 1968, respectively. [15] Duphaston was removed from the United States market in 1979, [90] and Gynorest is also no longer available in the United States. [91]

Society and culture

Generic names

Dydrogesterone is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name, while dydrogestérone is its DCF Tooltip Dénomination Commune Française and didrogesterone is its DCIT Tooltip Denominazione Comune Italiana. [2] [3] [15] [92] It was also originally known as isopregnenone. [2] [3] [15] [92] Dydrogesterone has also been referred to as retroprogesterone, but should not be confused with retroprogesterone. [93]

Brand names

Dydrogesterone is marketed mainly under the brand names Duphaston (alone) and Femoston (in combination with estradiol). [92] [3] It also is or has been marketed alone under the brand names Dabroston, Divatrone, Dufaston, Duvaron, Dydrofem, Femoston, Gestatron, Gynorest, Prodel, Retrone, Terolut and Zuviston and in combination with estradiol under the brand names Climaston, Femaston, and Femphascyl. [1] [3] [2] [15]

Availability

Dydrogesterone is available widely throughout the world. [92] [3] It is marketed in the United Kingdom, India, Ireland, South Africa, and Australia, but not in the United States, Canada, or New Zealand. [92] [3] The medication was previously available in the United States, [15] but has since been discontinued in this country. [16] Dydrogesterone is also available in elsewhere in Europe, as well as in Central and South America, Asia, and North Africa. [92] [3]

Related Research Articles

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<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand name Ortho Tri-Cyclen among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Tibolone</span> Chemical compound

Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such as hot flashes, accelerated skin aging, vaginal dryness, decreased muscle mass, and complications such as osteoporosis, sexual dysfunction, and vaginal atrophy. They are mostly caused by low levels of female sex hormones that occur during menopause.

<span class="mw-page-title-main">Promegestone</span> Chemical compound

Promegestone, sold under the brand name Surgestone, is a progestin medication which is used in menopausal hormone therapy and in the treatment of gynecological disorders. It is taken by mouth.

<span class="mw-page-title-main">Catamenial epilepsy</span> Epilepsy exacerbated during certain phases of the menstrual cycle

Catamenial epilepsy is a form of epilepsy in women where seizures are exacerbated during certain phases of the menstrual cycle. In rare cases, seizures occur only during certain parts of the cycle; in most cases, seizures occur more frequently during certain parts of the cycle. Catamenial epilepsy is underlain by hormonal fluctuations of the menstrual cycle where estrogens promote seizures and progesterone counteracts seizure activity.

<span class="mw-page-title-main">Trimegestone</span> Chemical compound

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.

<span class="mw-page-title-main">Progesterone (medication)</span> Medication and naturally occurring steroid hormone

Progesterone (P4), sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.

<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Estradiol valerate/cyproterone acetate</span> Combination drug

Estradiol valerate/cyproterone acetate (EV/CPA), sold under the brand names Climen and Femilar among others, is a combination product of estradiol valerate (EV), an estrogen, and cyproterone acetate (CPA), a progestogen, which is used in menopausal hormone therapy and as a birth control pill to prevent pregnancy. It is taken by mouth. Climen, which is used in menopausal hormone therapy, is a sequential preparation that contains 2 mg estradiol valerate and 1 mg CPA. It was the first product for use in menopausal hormone therapy containing CPA to be marketed and is available in more than 40 countries. Femilar, which is an estradiol-containing birth control pill, contains 1 to 2 mg estradiol valerate and 1 to 2 mg CPA, and has been approved for use in Finland since 1993.

References

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