dydrogesterone

Dydrogesterone
Systematic (IUPAC) name
	(9β,10α)-pregna-4,6-diene-3,20-dione
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	?
Legal status	?
Pharmacokinetic data
Bioavailability	28%
Metabolism	complete, 20-dihydrodydrogesterone (DHD) metabolite
Half-life	dydrogesterone (5-7 hours) & DHD (14-17 hours)
Identifiers
CAS number	152-62-5
ATC code	G03DB01
PubChem	CID 9051
DrugBank	DB00378
ChemSpider	8699
Chemical data
Formula	C21H28O2
Mol. mass	312.446 g/mol
	SMILES 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 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 ; Key:JGMOKGBVKVMRFX-HQZYFCCVSA-N ;
Physical data
Melt. point	144 °C (291 °F)
Boiling point	463 °C (865 °F)
Solubility in water	insoluble mg/mL (20 °C)
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/27 14:22:58」(JST)

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Dydrogesterone (INN, USAN, BAN), also known as 9β,10α-pregna-4,6-diene-3,20-dione, is a steroidal progestin. It is sold under the brand name Duphaston, which is manufactured by Abbott (formerly Solvay Pharmaceuticals).

Dydrogesterone was first introduced to the market in 1961, and is currently approved in over 100 countries worldwide. It has an estimated cumulative exposure of more than 10 million pregnancies.

Dydrogesterone is a potent, orally active progestogen indicated in a wide variety of gynaecological conditions related to progesterone deficiency. Although similar in molecular structure and pharmacological effects to endogenous progesterone. It is orally active at far lower doses. Its freedom from estrogenic, androgenic, anabolic, corticoid and other undesirable hormonal effects gives it additional benefits over most other synthetic progestogens.

The therapeutic use of dydrogesterone is closely related to its physiological action on the neuro-endocrine control of ovarian function, as well as on the endometrium. As such, it is indicated in all cases of relative or absolute endogeneous progesterone deficiency.

Dydrogesterone is to be withdrawn from the UK market from March 2008 for commercial reasons. Dydrogesterone was licensed for use in several indications,including threatened or recurrent miscarriage, dysfunctional uterine bleeding, and hormone replacement therapy.

Dydrogesterone has proven effective in the following conditions associated with progesterone deficiency:^{[citation needed]}

menstrual disorders
infertility due to luteal insufficiency
threatened and habitual abortion. Dydrogesterone is not approved for this indication by any regulatory body in US, Canada or Australia.
endometriosis
premenstrual syndrome

Dydrogesterone has also been registered as hormone replacement therapy (HRT) to counteract 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.

Indications[edit]

Menstrual disorders[edit]

Dysmenorrhoea

Primary or essential dysmenorrhoea is one of the most common gynaecological complaints of women during their reproductive years. Clinical studies have shown symptom relief and a reduction in pain with dydrogesterone treatment for dysmenorrhoea. (Aydar 1965, Fairweather 1963, Schellen 1967)

Secondary amenorrhoea

Secondary amenorrhoea is a symptom rather than a specific disease. Dydrogesterone adequately induces bleeding when the endometrium is sufficiently primed with estrogens. When estradiol levels are low, dydrogesterone treatment should be supplemented with estrogens.

Dysfunctional uterine bleeding and irregular cycles

Of the wide range of medications used to reduce heavy menstrual bleeding in patients with ovulatory cycles, oral progestogens like dydrogesterone are the most commonly prescribed. It prevents heavy bleeding.

Infertility, recurrent pregnancy loss and preterm birth[edit]

Dydrogesterone is used for luteal support in IVF protocols, for treatment of recurrent pregnancy loss, and for prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth.^[1]

Endometriosis[edit]

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. The efficacy of dydrogesterone on the lesions of endometriosis is less clear, but their number and severity does not seem to correlate with the severity of symptoms.

Premenstrual syndrome[edit]

Premenstrual syndrome (PMS) is characterised by a range of mood swings and physical symptoms.

Dydrogesterone effectively relieves a number of these.

Hormone replacement therapy[edit]

The principle behind HRT is twofold:

to actively increase the circulating levels of estrogens to control hot flushes
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.

Estrogens stimulate the growth of endometrial cells. In postmenopausal women with an intact uterus, estrogen monotherapy results in continued endometrial proliferation without the physiological secretory transformation normally induced by progesterone. This process is associated with an increased incidence of endometrial hyperplasia and carcinoma. Additional protection with progestogens is therefore mandatory in patients with an intact uterus who receive estrogen replacement therapy.

Dydrogesterone opposes the proliferative effect of estrogens on the endometrium and ensures conversion to a secretory pattern and cyclical shedding of the endometrium in sequential HRT regimens. As such dydrogesterone effectively guards against the development of endometrial hyperplasia. Unlike androgenic progestogens, dydrogesterone does not reverse the beneficial effects of 17β-oestradiol on lipid profiles and carbohydrate metabolism. In a continuous combined HRT regimen, dydrogesterone inhibits the proliferation of the endometrium so that it remains atrophic or inactive.

Chemistry[edit]

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. 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 activitity, metabolic stability, and the lack of estrogenic, androgenic glucocorticoid, and mineralocorticoid properties of dydrogesterone.

Pharmacokinetics[edit]

Dydrogesterone is readily absorbed after oral administration. T_max values vary between 0.5 and 2.5 hours.

Metabolisation of dydrogesterone is virtually complete. The main metabolic reaction is hydrogenation of the 20-keto group, resulting in 20-dihydrodydrogesterone (DHD), another potent progestogen. The levels of the main active metabolite DHD also peak about 1.5 hours after dosing.

After oral administration, plasma concentrations of DHD are substantially higher than those of the parent drug. The ratios of DHD/Dydrogesterone for AUC and C_max are in the order of 40 and 25, respectively. Absolute bio-availability is on average 28%.

All the metabolites of dydrogesterone retain the 4, 6-diene-3-one structure, and are metabolically stable. As such, dydrogesterone does not undergo aromatisation, which is consistent with its absence of estrogenic effects. Furthermore, dydrogesterone does not undergo 17α-hydroxylation, which explains its lack of androgenic effects.

Dydrogesterone has predictable pharmacokinetics. The single-dose kinetics are linear in the oral dose range of 5–20 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.

Dydrogesterone and its metabolites are excreted predominantly in urine. About 85% of an oral dose is excreted within 24 hours. The mean terminal half-lives od dydrogesterone and DHD vary between 5-7 and 14–17 hours, respectively.

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[edit]

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

It is orally active at low dosages.
It has selective progestogenic properties without any traditional hormonal activity.
The amount absorbed is more predictable than for progesterone, since it is not broken down as easily when passing through the digestive system.

Dydrogesterone is characterised by progestational and antiestrogenic activity. This is demonstrated by its ability to induce a secretory transformation in the endometrium of immature or ovariectomised animals after they have been primed with estrogens (cf. the Clauberg test). The oral progestogenic potency of dydrogesterone is 20 times higher than that of progesterone.

The progestational efficacy and potency of dydrogesterone was confirmed by standard test (i.e. delay of menses and induction of withdrawal bleeding). The benefits of estrogen or other target organs are not compromised by dydrogesterone.

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

no virilisation (acne, voice changes, hirsutism) of the adult female
no virilising effects on the genital tract of the female foetus
no effect on the fertility of the offspring.

Dydrogesterone is not converted into estrogen, and has no adverse estrogenic effects on fertility or sexual development.

At recommended doses, dydrogesterone has no effect on ovulation in healthy women:

the biphasic pattern of the basal body temperature is maintained
normal ovulatory rise in estrogen and pregnanediol
normal premenstrual biopsy
no modification of vaginal cytology
cytological evidence of ovulation
the formation of the corpus luteum has been confirmed by laparotomy

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

Toxicology[edit]

No serious or unexpected toxicity has been observed with dydrogesterone. In acute toxicity studies, the LD₅₀ doses in rats exceeded 4,640 mg/kg for the oral route.

There was no evidence of mutagenic potential in the Ames test.

Adverse Reactions and Side effects[edit]

The most commonly reported adverse drug reactions of patients treated with dydrogesterone in clinical trials of indications without estrogen treatment are migraines/headache, nausea, menstrual disorders and breast pain/tenderness.

The use of progestins, in particular medroxyprogesterone, in treating post-menopausal symptoms have been associated with increased risk of blood clots and breast cancer in a study carried out by the Women's Health Initiative. While the study did not study dydrogesterone, it is possible, but not certain, that it too increases these risks.

References[edit]

^ 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.

UpToDate Contents

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1. 不育症の男女のマネージメント management of couples with recurrent pregnancy loss
2. 閉経後の継続的ホルモン療法 continuous postmenopausal hormone therapy
3. 月経前症候群および月経前不快気分障害の治療 treatment of premenstrual syndrome and premenstrual dysphoric disorder

English Journal

Progestins as endocrine disrupters in aquatic ecosystems: Concentrations, effects and risk assessment.

Fent K1.
Environment international.Environ Int.2015 Aug 11;84:115-130. doi: 10.1016/j.envint.2015.06.012. [Epub ahead of print]
In aquatic ecosystems, progesterone (P4) and synthetic progestins (gestagens) originate from excretion by humans and livestock. Synthetic progestins are used for contraception and as P4 for medical treatments as well. Despite significant use, their ecotoxicological implications are poorly understood
PMID 26276056

Modulation of Cytokine Production by the Dydrogesterone Metabolite Dihydrodydrogesterone.

Raghupathy R1, Al-Azemi M2.
American journal of reproductive immunology (New York, N.Y. : 1989).Am J Reprod Immunol.2015 Aug 7. doi: 10.1111/aji.12418. [Epub ahead of print]
PROBLEM: Previous studies have shown that dydrogesterone, the orally administered progestogen, upregulates the production of Th2 cytokines and downregulates Th1 cytokine production. This study was designed to ascertain whether dihydrodydrogesterone (DHD), the major metabolite of dydrogesterone, is s
PMID 26250154

Effect of Progesterone, Its Hydroxylated and Methylated Derivatives, and Dydrogesterone on Lipid Bilayer Membranes.

Abboud R1, Greige-Gerges H, Charcosset C.
The Journal of membrane biology.J Membr Biol.2015 Aug;248(4):811-24. doi: 10.1007/s00232-015-9803-z. Epub 2015 Apr 25.
The interaction of progesterone (PG), 17-hydroxyprogesterone (17-OHPG), 21-hydroxyprogesterone (21-OHPG), medroxyprogesterone (MP), medroxyprogesterone acetate (MPA), and dydrogesterone (DYG), with zwitterionic dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposome, was investigated as a func
PMID 25911547

Japanese Journal

P1-37-10 IVF-ETでの黄体補充に経口dydrogesteroneは有効か(Group71 生殖補助医療2,一般演題,第63回日本産科婦人科学会学術講演会)

福原理恵,福井淳史,飯野香理,木村秀崇,水沼英樹
日本産科婦人科學會雜誌 63(2), 697, 2011-02-01
NAID 110008509514

Meningioma in a Woman Receiving Hormone Therapy

MURATA Yoriko,TAKEUCHI Seisho,YOSHIDA Shoji,MIYOSHI Isao
Internal medicine 42(12), 1267, 2003-12-01
NAID 130000767046

Related Pictures

[Loose_2006-1] 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.

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