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. It is taken by mouth.
Side effects of dydrogesterone include menstrual irregularities, headache, nausea, breast tenderness, and others. Dydrogesterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. The medication is an atypical progestogen and does not inhibit ovulation. It has weak antimineralocorticoid activity and no other important hormonal activity.
Dydrogesterone was developed in the 1950s and introduced for medical use in 1961. 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. The medication was previously available in the United States, but it has been discontinued in that country.
Medical uses Dydrogesterone has proven effective in a variety of conditions associated with progesterone deficiency, Infertility due to luteal insufficiency including threatened miscarriage, habitual or recurrent miscarriage, Menstrual disorders premenstrual syndrome, and endometriosis. Dydrogesterone has also been registered as a component of menopausal hormone therapy 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.
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. 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.
Dydrogesterone has shown reasonable efficacy in relieving a number of premenstrual syndrome symptoms like mood swings and physical symptoms. 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.
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. 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.
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.
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.
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.
Available forms
Dydrogesterone is available in the form of 10 mg oral tablets both alone and in combination with estradiol.
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. The use of progestins, in particular medroxyprogesterone acetate, in treating postmenopausal 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.
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.
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.
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 selective progestogen, and due to its unique structure, unlike progesterone and many other progestins, binds almost exclusively to the progesterone receptor (PR). The affinity of dydrogesterone for the PR is relatively low at about 16% of that of progesterone. 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. 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. 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. The major active metabolite of dydrogesterone, 20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone. As with other progestogens, dydrogesterone has functional antiestrogenic effects in certain tissues, for instance in the endometrium, and induces endometrial secretory transformation.
Dydrogesterone does not bind importantly to the androgen, estrogen, or glucocorticoid receptor. As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity. Similarly to progesterone however, dydrogesterone binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so. 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. The medication and 20α-DHD do not inhibit 5α-reductase. 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.
Atypical progestogenic profile Due to its progestogenic activity, dydrogesterone can produce antigonadotropic effects at sufficient doses in animals. 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. 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). 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. This included prevention of the mid-cycle LH and FSH peaks and the luteal-phase rise in body temperature and pregnanediol excretion. Nonetheless, the overall consensus among researchers seems to be that dydrogesterone does not inhibit ovulation in women. The apparent inability of dydrogesterone to prevent ovulation is in contrast to all other clinically used progestogens except trengestone, which is closely related to dydrogesterone. 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).