Dydrogesterone, sold under the brand name Duphaston among others,[6] is a progestinmedication 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]
Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others.Dydrogesterone is a progestin, or a syntheticprogestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like
Dydrogesterone was developed in the 1950s and introduced for medical use in 1961.[10] It is available widely throughout Europe, no longer available in the United Kingdom, since 2008 and is also marketed in Australia and elsewhere in the world.[10] The medication was previously available in the United States,[10] but it has been discontinued in that country.[11]
Medical uses
Dydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency,[12]Infertility due to luteal insufficiency[13][14] including threatened miscarriage,[15] habitual or recurrent miscarriage,[16]Menstrual disorders[17] premenstrual syndrome,[18] and endometriosis.[19] Dydrogesterone has also been registered as a component of menopausal hormone therapy[20] 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. 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.[21]
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.[22] 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.
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.[33][34] 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. Studies have not shown any incidence of decreased fertility due to dydrogesterone at therapeutic dose. The Ames test found no evidence of any potential mutagenic or toxicity properties.[37]
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. There are no antidotes to overdose, and treatment should be based on symptoms.In acute toxicity trials, the LD50 doses in rats were in excess of 4,640 mg/kg orally.[38][39]
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.
Pharmacology
Pharmacodynamics
Dydrogesterone is a highly selectiveprogestogen, and due to its unique structure, unlike progesterone and many other progestins, binds almost exclusively to the progesterone receptor (PR).[40] The affinity of dydrogesterone for the PR is relatively low at about 16% of that of progesterone.[41] However, in vivo, dydrogesterone is comparatively much more potent by the oralroute, with an equivalent dose, in terms of endometrialproliferation, that is 10 to 20 times lower than that of progesterone.[42] 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.[8] 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.[43] The major active metabolite of dydrogesterone, 20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone.[43] 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.[41][43] As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity.[40][7][43] Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so.[7][43] Like other progestins but unlike progesterone, which forms
Atypical progestogenic profile
Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals.[45] 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][9][46] Oral doses of dydrogesterone of 5 to 40 mg/day on days 5 to 25 of the cycle fail to suppress ovulation (assessed by urinarypregnanediol 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).[47][9]
Atypical progestogenic profile
Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals.[45] 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][9][46] Oral doses of dydrogesterone of 5 to 40 mg/day on days 5 to 25 of the cycle fail to suppress ovulation (assessed by urinarypregnanediol 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).[47][9]
Other activity
Dydrogesterone weakly stimulates the proliferation of MCF-7breast cancercellsin vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[61] Certain other progestins are also active in this assay, whereas progesterone acts neutrally.[61] 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.[62]
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%.[63]Tmax values vary between 0.5 and 2.5 hours.[64]Steady state is attained after 3 days of treatment.The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose.[65]
A single intramuscular injection of 100 mg dydrogesterone in microcrystallineaqueous suspension has been found to have a duration of action
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%.[63]Tmax values vary between 0.5 and 2.5 hours.[64]Steady state is attained after 3 days of treatment.The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose.[65]
A single intramuscular injection of 100 mg dydrogesterone in microcrystallineaqueous 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.[9]
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.[2][7]
Metabolism
The metabolism of dydrogesterone occurs in the liver.[66] It is virtually completely metabolized.[66] 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.[4] With oral administration of dydrogesterone, circulating levels of 20α-DHD are substantially higher than those of dydrogesterone.[43] 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.[43] For these reasons, despite the lower relative progestogenic potency of 20α-DHD, dydrogesterone may act as a prodrug of this metabolite.
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.[9]
Miscellaneous
The pharmacokinetics of dydrogesterone have been reviewed.[7]
Chemistry
Dydrogesterone, also known as 6-dehydro-9β,10α-progesterone or as 9β,10α-pregna-4,6-diene-3,20-dione, is a syntheticpregnanesteroid and a derivative of progesterone and retroprogesterone (9β,10α-progesterone).[67][68] 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.[52] 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).[67][68] 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][40]
Analogues
Other retroprogesterone derivatives, and analogues of dydrogesterone, include trengestone (1,6-didehydro-6-chlororetroprogesterone) and Ro 6-3129 (16α-ethylthio-6-dehydroretroprogesterone).[67][68]
Synthesis
Dydrogesterone is synthesized and manufactured by treatment of progesterone with ultraviolet light exposure.[40]
Chemical syntheses of dydrogesterone have been published.[69]
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,[8] but it has enhanced oral bioavailability.It is estimated that during the period from 1977 to 2005[70] 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.[10] Subsequently, it was introduced in the United States as Duphaston and Gynorest in 1962 and 1968, respectively.[10] Duphaston was removed from the United States market in 1979,[71] and Gynorest is also no longer available in the United States.[72]
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.[67][68][10][73] It was also originally known as isopregnenone.[67][68][10][73] Dydrogesterone has also been referred to as retroprogesterone, but should not be confused with retroprogesterone.[74]
Brand names
Dydrogesterone is marketed mainly under the brand names Duphaston (alone) and Femoston (in combination with estradiol).[73][68] 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.[6][68][67][10]
Availability
Dydrogesterone is available widely throughout the world.[73][68] It is marketed in the United Kingdom, India, Ireland, South Africa, and Australia, but not in the United States, Canada, or New Zealand.[73][68] The medication was previously available in the United States,[10] but has since been discontinued in this country.[11] Dydrogesterone is also available in elsewhere in Europe, as well as in Central and South America
See also
Estradiol/dydrogesterone
Further reading
References
1.Progestogens in Obstetrics and Gynecology Springer, 2015^
3.Dydrogesterone metabolism in human liver by aldo-keto reductases and cytochrome P450 enzymes Xenobiotica; the Fate of Foreign Compounds in Biological Systems, October 2016^
4.Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 Chemico-Biological Interactions, May 2011^
5.Progestogens in menopausal hormone therapy Przeglad Menopauzalny = Menopause Review, June 2015^
7.Pharmacology of estrogens and progestogens: influence of different routes of administration Climacteric, August 2005^
8.Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium Maturitas, December 2009^
9.Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Drugs International Encyclopaedia of Pharmacology and Therapeutics., 1972^
21.Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study Gynecological Endocrinology, November 2007^
22.The place of dydrogesterone in the treatment of endometriosis and adenomyosis Maturitas, December 2009^
23.Effective post-laparoscopic treatment of endometriosis with dydrogesterone Gynecological Endocrinology, October 2007^
24.Cyclic progestin therapy for the management of mastopathy and mastodynia Gynecological Endocrinology, December 2001^
25.Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial European Journal of Obstetrics, Gynecology, and Reproductive Biology, March 2015^
26.Oral dydrogesterone vs. vaginal progesterone capsules for luteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis JBRA Assisted Reproduction, June 2018^
27.Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial Human Reproduction, December 2018^
28.A systematic review of dydrogesterone for the treatment of threatened miscarriage Gynecological Endocrinology, December 2012^
29.Postmenopausal hormone therapy: an Endocrine Society scientific statement The Journal of Clinical Endocrinology and Metabolism, July 2010^
30.Use of dydrogesterone in hormone replacement therapy Maturitas, December 2009^
39.A new class of hormonally active steroids Nature, April 1960^
40.Classification and pharmacology of progestins Maturitas, December 2003^
41.Recent advances in structure of progestins and their binding to progesterone receptors Journal of Enzyme Inhibition and Medicinal Chemistry, February 2015^
42.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, January 2006^
43.Selectivity and potency of the retroprogesterone dydrogesterone in vitro Steroids, May 2011^
44.The steroid hormone dydrogesterone inhibits myometrial contraction independently of the progesterone/progesterone receptor pathway Life Sciences, August 2018^
45.Some studies of the endocrine properties of dydrogesterone Steroids, January 1966^
47.Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide Contraception, December 2011^
48.Influence of dydrogesterone on the activity of the nonpregnant human uterus American Journal of Obstetrics and Gynecology, April 1970^
53.Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis Gynecological Endocrinology, February 2017^
55.Progesterone, progestins and the breast in menopause treatment Climacteric, August 2018^
56.Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety Maturitas, September 2013^
57.Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations Climacteric, October 2009^
58.Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence Current Opinion in Endocrinology, Diabetes and Obesity, December 2015^
59.Essentials of Menopause Management Springer, 2017^
60.Endometrial cancer in postmenopausal women using estradiol-progestin therapy Obstetrics and Gynecology, December 2009^
61.Possible role of PGRMC1 in breast cancer development Climacteric, October 2013^
62.Progesterone and Breast Cancer Endocrine Reviews, April 2020^
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.[18] 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.[24]
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.[25] 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.[26][27]
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.[16][28]
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.[29]
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.[30]
Available forms
Dydrogesterone is available in the form of 10 mg oraltablets both alone and in combination with estradiol.[31][32]
sedative
neurosteroid
metabolites, dydrogesterone is not able to be metabolized in a similar way, and for this reason, is non-sedative.
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.
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.[50][51] However, a related retroprogesterone derivative, trengestone, likewise does not inhibit ovulation or produce a hyperthermic effect but rather has an inducing effect on ovulation.[52]
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).[53][54][55] 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.[56][57] 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).[58][59][60]
Other activity
Dydrogesterone weakly stimulates the proliferation of MCF-7breast cancercellsin vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[61] Certain other progestins are also active in this assay, whereas progesterone acts neutrally.[61] 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.[62]
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.
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.
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.[50][51] However, a related retroprogesterone derivative, trengestone, likewise does not inhibit ovulation or produce a hyperthermic effect but rather has an inducing effect on ovulation.[52]
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).[53][54][55] 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.[56][57] 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).[58][59][60]
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.[2][7]
Metabolism
The metabolism of dydrogesterone occurs in the liver.[66] It is virtually completely metabolized.[66] 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.[4] With oral administration of dydrogesterone, circulating levels of 20α-DHD are substantially higher than those of dydrogesterone.[43] 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.[43] For these reasons, despite the lower relative progestogenic potency of 20α-DHD, dydrogesterone may act as a prodrug of this metabolite.[43]
The metabolism of dydrogesterone differs from progesterone.[9] Whereas the major metabolite of progesterone is pregnanediol, the corresponding derivative of dydrogesterone, retropregnanediol, cannot be detected in urine with oral administration of dydrogesterone.[9] 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.[5]
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.[9]
Miscellaneous
The pharmacokinetics of dydrogesterone have been reviewed.[7]
The metabolism of dydrogesterone differs from progesterone.[9] Whereas the major metabolite of progesterone is pregnanediol, the corresponding derivative of dydrogesterone, retropregnanediol, cannot be detected in urine with oral administration of dydrogesterone.[9] 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.[5]
