Dydrogesterone

Dydrogesterone

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

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

Dydrogesterone has selective progestational activity and does not inhibit ovulation. The greater rigidity of dydrogesterone also positively affects its selectivity, while natural progesterone is less selective, existing in different conformations that more easily bind to different receptors. As a consequence of its better bioavailability and the progestational activity of its main metabolites (20-, 21- and 16-hydroxy derivatives), the equivalent dose of dydrogesterone is 10–20 times lower than that of oral micronized progesterone.

Dydrogesterone is used as an effective, orally active progestogen for gynaecological conditions related to a wide variety of progesterone deficiencies in pregnant women. The molecular structure and pharmacological effects are somewhat similar to endogenous progesterone, although in smaller amounts it is found to be orally active. Its freedom from hormonal effects like those related to corticoid, androgenic, estrogenic, anabolic, and other effects gives dydrogesterone an advantage over other synthesized progestogens.

Dydrogesterone when used therapeutically is closely related to its physiological action on the neuro-endocrine control of ovarian function, as well as on the endometrium. This is an indication in all cases of endogeneous progesterone deficiency - relative or absolute. The molecule was licensed for use in several indications, including threatened or recurrent miscarriage, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhoea, irregular cycles, pre-menstrual syndrome and also as a hormone replacement therapy. Dydrogesterone has proven effective in the following conditions associated with progesterone deficiency:

• Infertility due to luteal insufficiency
• Threatened miscarriage
• Habitual or recurrent miscarriage.
• Menstrual disorders
• Premenstrual syndrome
• Endometriosis

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

Medical Uses

Menstrual Disorders

Dysmenorrhea

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

Secondary amenorrhoea

Secondary amenorrhoea is not a specific disease, but is instead a symptom. Dydrogesterone has been found to adequately induce bleeding within a sufficiently estrogen-primed endometrium. When estradiol levels are found to be low, dydrogesterone treatment is more effective when supplemented with estrogens.

Dysfunctional uterine bleeding and irregular cycles

Apart from a wide variety of medications in use to reduce heavy menstrual bleeding in patients with ovulatory cycles, oral progestogens like dydrogesterone have been found to be the most commonly prescribed as it has been found to prevent heavy bleeding.

Infertility due to luteal insufficiency

Oral dydrogesterone is effective drug, well tolerated and accepted among patients and can be considered for routine luteal support. Advantage of dydrogesterone is oral administration, easy to use and better patient compliance which results in high satisfaction score of oral dydrogesterone in luteal support of IVF/ICSI cycles. According to the Cochrane review 2011, there is clinical evidence in favor of dydrogesterone over micronized progesterone for luteal phase support. Dydrogesterone is used for luteal support in IVF protocols, for treatment of recurrent pregnancy loss.

Miscarriage

Threatened miscarriage is defined as bleeding during the first 20 weeks of pregnancy while the cervix is closed. It is the most common complication in pregnancy, occurring in 20% of all pregnancies. Recurrent abortion is defined as the loss of three or more consecutive pregnancies. Dydrogesterone is associated with approximately two-fold significant reduction in the miscarriage rate as compared to standard care in threatened and recurrent miscarriages with minimal side effects.

Endometriosis

Endometriosis is a chronic disease which can cause severe, progressive, and at times, incapacitating dysmenorrhoea, pelvic pain, dyspareunia and infertility. Dydrogesterone relieves pain without inhibiting ovulation, so that patients are able to become pregnant during treatment. Dydrogesterone is particularly suitable in cases where the woman desires to become pregnant and to prevent bleeding problems. 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. The amount and duration of menstrual bleeding is also significantly reduced, and from the end of the third month onwards, bleeding was considered normal in the majority of patients. Improvement of endometriosis was observed in 71% of patients and cure in 21%.

Premenstrual syndrome

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

Hormone replacement therapy

The objective behind hormone replacement therapy is to actively increase the circulating levels of estrogen to control hot flushes and to prevent the long-term effects of the menopause, such as bone resorption and unfavourable changes in blood lipids. The administration of 17β-oestradiol halts, or reverses atrophic changes that occur due to the loss of endogenous oestradiol during the menopause.

Estrogen promotes endometrial cell growth and in postmenopausal women with an intact uterus, estrogen monotherapy results in continued endometrial development without the physiological secretory changes normally brought on by progesterone. This action is associated with an increased incidence of endometrial hyperplasia and carcinoma. Additional protection with progestogens is therefore important in patients with an intact uterus who receive estrogen replacement therapy. Dydrogesterone counters the proliferative effect of estrogens on the endometrium and ensures the transition to a secretory pattern and cyclical shedding of the endometrium in serial HRT regimes. Dydrogesterone effectively protects against the ontogenesis of endometrial hyperplasia. Unlike androgenic progestogens, dydrogesterone does not reverse the benefits brought on by 17β-oestradiol on lipid profiles and carbohydrate metabolism. In a continuous, combined HRT regimen, dydrogesterone retards the proliferation of the endometrium so that it remains atrophic or inactive.

Pregnancy

Pregnancy

Dydrogesterone has been prescribed and used in over 10 million pregnancies worldwide. There have been no harmful effects exhibited due to the use of dydrogesterone while pregnant. Dydrogesterone is safe to use during pregnancy only when prescribed and indicated by a medical practitioner.

Fertility

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

Over dosage

There is not enough clinical data to support overdose in humans. 360 mg is the maximum dose taken to date by humans and dydrogesterone was found to be well-tolerated at that oral dose. Additionally, there are no antidotes to over dosage and subsequent treatments should be based on patient symptoms.

Toxicology

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

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

Side effects

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

The use of progestins, in particular medroxyprogesterone acetate, 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 involve dydrogesterone, it is possible, but not certain, that it too increases these risks.

Chemistry

Dydrogesterone was first synthesised by Duphar in the 1950s. Although its molecular structure is almost identical to that of natural progesterone, its unique design makes it a potent, orally active progestogen. In the dydrogesterone molecule, the hydrogen atom at carbon 9 is in the beta position and the methyl group at carbon 10 is in the alpha position - a reverse of the progesterone structure, hence the term 'retro' progesterone. Furthermore, it has a second double bond between carbon 6 and carbon 7 (the 4, 6-diene-3-one configuration). These small differences in chemical structure account for the improved oral activity, metabolic stability, and the lack of estrogenic, androgenic, glucocorticoid, and mineralocorticoid properties of dydrogesterone.

Pharmacokinetics

Metabolism

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

After oral administration, it was found that plasma concentrations of dihydrodydrogesterone were substantially heightened than those of the primary drug. The ratios of DHD and Dydrogesterone for AUC and Cmax are in the order of 40 and 25, respectively. Absolute bioavailability is on average 28%. All the metabolites of dydrogesterone retain the 4, 6-diene-3-one structure, and are metabolically stable. As such, dydrogesterone does not undergo aromatisation, which is consistent with its absence of estrogenic effects. Furthermore, dydrogesterone does not undergo 17α-hydroxylation, which explains its lack of androgenic effects.

Elimination and dependencies

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

Dydrogesterone has predictable pharmacokinetics. The single-dose kinetics are linear in the oral dose range of 2.5–10 mg. The pharmacokinetics do not change during repeated administration of up to 20 mg dydrogesterone once daily. Steady state is attained after 3 days of treatment. In HRT, dydrogesterone is administered together with an estrogen. Therefore, the interaction between dydrogesterone and estrogens has been assessed, and no clinically significant interaction has been observed.

Pharmacology

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

• 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 showed:

• 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.

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

History

Dydrogesterone is a steroidal progestin first introduced to the market in 1961. It is unique, being the only retrosteroid that is commercially available and its molecular structure is closely related to that of natural progesterone, but it has enhanced oral bioavailability.

It is estimated that during the period from 1977 to 2005 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 (formerly known as Solvay Pharmaceuticals). Dydrogesterone is not available in UK and USA market due to commercial reasons.

Sources

Dydrogesterone is manufactured by treating progesterone with ultra-violet light, leading to a change in the spatial structure. It is produced from the plant steroids, Dioscorea mexicana, a plant of the yam family native to Mexico. Dioscorea contains a sterol called diosgenin. Diosgenin is converted to progesterone. Hence, the source is always natural.

See also

• Trengestone
• Retroprogesterone
• Medrogestone