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Dydrogesterone molecule ball.png
Clinical data
Trade namesDuphaston, others
SynonymsIsopregnenone; Dehydroprogesterone; Didrogesteron; 6-Dehydroretroprogesterone; 9β,10α-Pregna-4,6-diene-3,20-dione; NSC-92336[1][2]
AHFS/Drugs.comInternational Drug Names
Routes of
By mouth
Drug classProgestin; Progestogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding? (probably to albumin)[5][6]
MetabolismHepatic: AKR1C1, AKR1C3, CYP3A4[3][4]
Metabolites20α-DHD (exclusively via AKR1C1 and AKRC13)[4]
Elimination half-lifeParent: 5–7 hours[7]
Metabolite: 14–17 hours[7]
CAS Number
PubChem CID
ECHA InfoCard100.005.280 Edit this at Wikidata
Chemical and physical data
Molar mass312.446 g/mol g·mol−1
3D model (JSmol)
Melting point144 °C (291 °F)
Boiling point463 °C (865 °F)
Solubility in waterInsoluble 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.[6] It is taken by mouth.[6]

Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others.[8][9] Dydrogesterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[6][10] The drug is an atypical progestogen and does not inhibit ovulation.[6][11] It has weak antimineralocorticoid activity and no other important hormonal activity.[6][10]

Dydrogesterone was developed in the 1950s and introduced for medical use in 1961.[12] It is available widely throughout Europe, including in the United Kingdom, and is also marketed in Australia and elsewhere in the world.[2][12] The drug was previously available in the United States,[12] but it has been discontinued in this country.[13]

Medical uses

Dydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency,[14] Infertility due to luteal insufficiency[15][16] including threatened miscarriage,[17] habitual or recurrent miscarriage,[18] Menstrual disorders[19] premenstrual syndrome,[20] and endometriosis.[21] Dydrogesterone has also been registered as a component of menopausal hormone therapy[22] to counteract the effects of unopposed estrogen on the endometrium in women 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.[23] 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.[24] 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.[25]

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.[26] 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.[23] The amount and duration of menstrual bleeding is also significantly reduced, and from the end of the third month onwards, bleeding was considered normal in the majority of patients. Improvement of endometriosis was observed in 71% of patients and cure in 21%.

Dydrogesterone has shown reasonable efficacy in relieving a number of premenstrual syndrome symptoms like mood swings and physical symptoms.[20] 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.[27]

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.[28] 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.[29]

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.[18][30]

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.[31]

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.[32]

Available forms

Dydrogesterone is available in the form of 10 mg oral tablets both alone and in combination with estradiol.[33][34]


Side effects

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.[8][9] The use of progestins, in particular medroxyprogesterone acetate, in treating postmenopausal symptoms have been associated with increased risk of blood clots[35] 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.[36]

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.[37] Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose.[37] The Ames test found no evidence of any potential mutagenic or toxicity properties.[38]


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.[37] In acute toxicity trials, the LD50 doses in rats were in excess of 4,640 mg/kg orally.[39][40]


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.



20α-Dihydrodydrogesterone, 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).[41] The affinity of dydrogesterone for the PR is relatively low at about 16% of that of progesterone.[42][43] However, in vivo, dydrogesterone is much more potent in comparison via the oral route, with an equivalent dose, in terms of endometrial proliferation, that is 10 to 20 times lower than that of progesterone.[44] 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.[45] Dydrogesterone binds to and activates both of the major isoforms of the PR, the PR-A and PR-B, with a similar selectivity ratio between the two receptors as that of progesterone and with lower efficacy at the receptors relative to progesterone.[42] The major active metabolite of dydrogesterone, 20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone.[42] As with other progestogens, dydrogesterone has functional antiestrogenic effects in certain tissues, for instance in the endometrium, and induces endometrial secretory transformation.[6]

Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals.[46] However, it does not suppress gonadotropin secretion or inhibit ovulation at typical clinical dosages in humans;[6][47] 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).[48] 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.[48][49] In addition, similarly to trengestone but unlike all other progestogens, dydrogesterone does not increase body temperature (i.e., it has no hyperthermic effect).[6][49][50] Also, whereas all other assessed progestins are associated with an increased risk of breast cancer when combined with an estrogen in postmenopausal women, neither oral progesterone nor dydrogesterone are associated with a significantly increased risk of breast cancer (although the risk of breast cancer is non-significantly increased with dydrogesterone).[51][52][53] 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.[54][55] However, as with oral progesterone, dydrogesterone offers inferior endometrial protection relative to other progestogens such as medroxyprogesterone acetate and norethisterone acetate, with a significantly increased risk of endometrial cancer in combination with an estrogen with long-term therapy (>5 years).[56][57][58]

Dydrogesterone does not bind importantly to the androgen, estrogen, or glucocorticoid receptor.[43][42] As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity.[41][6][42] Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so.[6][42] Like other progestins but unlike progesterone, which forms sedative neurosteroid metabolites, dydrogesterone is not able to be metabolized in a similar way, and for this reason, is non-sedative.[6] The medication and 20α-DHD do not inhibit 5α-reductase.[42] Dydrogesterone has been found to inhibit myometrium contractility via an undefined progesterone receptor-independent mechanism in vivo in pregnant rats and in vitro in human tissue at concentrations at which progesterone and other progestogens do not.[59]

Affinities of dydrogesterone and related steroids[42]
Progestogen PR AR GR ERα
Ki (nM) RBA (%) Ki (nM) RBA (%) Ki (nM) RBA (%) Ki (nM)
Dydrogesterone 125.9 15.9 251.2 10.0 361.2 17.5 >10,000
20α-Dihydrodydrogesterone 125.9 15.9 3162.3 0.8 3162.3 2.0 >10,000
Progesterone 20.0 100 25.1 100 63.1 100 >10,000


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%.[60] Tmax values vary between 0.5 and 2.5 hours.[61] Steady state is attained after 3 days of treatment.[37] The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose.[37] 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.[5][6]

Dydrogesterone is virtually completely metabolized, which occurs in the liver.[62] The primary metabolic pathway is the hydrogenation of the 20-keto group mainly by AKR1C1 and to a lesser extent AKR1C3, resulting in 20α-DHD, which is a potent progestogen similarly to dydrogesterone, albeit with much lower potency.[4] 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 to dydrogesterone for AUC and Cmax are on the order of 40:1 and 25:1, respectively.[42] As such, dydrogesterone appears to be a prodrug of 20α-DHD.[42] All of the metabolites of dydrogesterone retain the 4,6-diene-3-one structure, and are metabolically stable. As such, dydrogesterone does not undergo aromatization, which is consistent with its absence of estrogenic effects.

The mean elimination half-lives of DHD and dydrogesterone vary between 14 to 17 hours and 5 to 7 hours, respectively.[7] Dydrogesterone and its metabolites are excreted predominantly in urine. Total clearance of plasma is at a rate of 6.4 L/min. Within 72 hours, excretion is virtually complete. DHD is preponderantly present in the urine as a conjugate of glucuronic acid. Approximately 85% of the oral dose is successfully egested from the body within 24 hours.

The pharmacokinetics of dydrogesterone have been reviewed.[6][63]


A 3D schematic representation of the chemical structures of progesterone (top) and dydrogesterone (bottom), showing the retrosteroid spatial configuration of dydrogesterone.[6][41]

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).[1][2] 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.[49] 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.[6] Dydrogesterone also has an additional double bond between the C6 and C7 positions (4,6-dien-3-one configuration).[1][2] While its chemical structure is very close to that of progesterone, these small differences result in dydrogesterone having improved oral activity and metabolic stability, among other differences, in comparison to progesterone.[6][41]


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


Dydrogesterone is synthesized and manufactured by treatment of progesterone with ultraviolet light exposure.[41]

Chemical syntheses of dydrogesterone have been published.[63]


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,[64] but it has enhanced oral bioavailability. It is estimated that during the period from 1977 to 2005[65] around 38 million women were treated with dydrogesterone and that fetuses were exposed to dydrogesterone in utero in more than 10 million pregnancies. It has been approved in more than 100 countries worldwide. It is commercially marketed under the brand name Duphaston and manufactured by Abbott after it took over Solvay Pharmaceuticals. Dydrogesterone was first introduced, by Duphar, as Duphaston in the United Kingdom in 1961.[12] Subsequently, it was introduced in the United States as Duphaston and Gynorest in 1962 and 1968, respectively.[12] Duphaston was removed from the United States market in 1979,[66] and Gynorest is also no longer available in the United States.[67]

Society and culture

Generic names

Dydrogesterone is the generic name of the drug and its INN, USAN, and BAN, while dydrogestérone is its DCF and didrogesterone is its DCIT.[1][2][12][68] It was also originally known as isopregnenone.[1][2][12][68] Dydrogesterone has also been referred to as retroprogesterone, but should not be confused with retroprogesterone.[69]

Brand names

Dydrogesterone is marketed mainly under the brand names Duphaston (alone) and Femoston (in combination with estradiol).[68][2] It also is or has been marketed alone under the brand names Dabroston, Dufaston, Duvaron, Gestatron, Gynorest, Prodel, Retrone, and Terolut and in combination with estradiol under the brand names Climaston, Femaston, and Femphascyl.[68][2][1][12]


Dydrogesterone is available widely throughout the world.[68][2] It is marketed in the United Kingdom, Ireland, South Africa, and Australia, but not in the United States, Canada, or New Zealand.[68][2] The drug was previously available in the United States,[12] but has since been discontinued in this country.[13] Dydrogesterone is also available in elsewhere in Europe, as well as in Central and South America, Asia, and North Africa.[68][2]


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