Pharmacodynamics (20α-DHD), the main
active form of dydrogesterone. 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. The major
active metabolite of dydrogesterone,
20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to dydrogesterone.
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). 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. However, a related retroprogesterone derivative, trengestone, likewise does not inhibit ovulation or produce a hyperthermic effect but rather has an
inducing effect on ovulation. 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). 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. 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).
Other activity 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). Certain other progestins are also active in this assay, whereas
progesterone acts neutrally.
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%.
Tmax values vary between 0.5 and 2.5 hours.
Steady state is attained after 3 days of treatment. 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 virtually completely metabolized. 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. With oral administration of dydrogesterone, circulating levels of 20α-DHD are substantially higher than those of dydrogesterone. 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. For these reasons, despite the lower relative progestogenic potency of 20α-DHD, dydrogesterone may act as a
prodrug of this metabolite. The metabolism of dydrogesterone differs from progesterone. Whereas the major
metabolite of progesterone is
pregnanediol, the corresponding derivative of dydrogesterone, retropregnanediol, cannot be detected in
urine with oral administration of dydrogesterone. 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.
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.
Miscellaneous The
pharmacokinetics of dydrogesterone have been reviewed. ==Chemistry==