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] Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others.

[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.

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.

[27] Endometriosis is a chronic disease which can cause severe, progressive, and at times, incapacitating dysmenorrhea, pelvic pain, dyspareunia and infertility.

[29] Oral dydrogesterone is an effective medication, well tolerated and accepted among patients, and can be considered for routine luteal support.

[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.

Additional protection with progestogens is therefore important in patients with an intact uterus who receive estrogen therapy.

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.

[36][37] 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.

[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.

[45] As with other progestogens, dydrogesterone has functional antiestrogenic effects in certain tissues, for instance in the endometrium, and induces endometrial secretory transformation.

[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.

[48] Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals.

[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] This included prevention of the mid-cycle LH and FSH peaks and the luteal-phase rise in body temperature and pregnanediol excretion.

[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.

[62][63][64] 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] 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.

[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.

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.