Gestodene

Contraception

Gestodene is androgenically neutral, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g. acne, hirsutism, weight gain) often associated with second-generation contraceptive pills, such as those containing levonorgestrel.

The synthetic estrogen dosage in third-generation contraceptive pills (including those containing gestodene) is lower than that in second-generation oral contraceptives, reducing the likelihood of weight gain, breast tenderness and migraine.

Third-generation oral contraceptives are also suitable for use in patients with diabetes or lipid disorders because they have minimal impact on blood glucose levels and the lipid profile.

Available forms

Products containing gestodene include:

Side effects

Women who take oral contraceptives containing gestodene are 5.6 times as likely to develop thromboembolism than women who do not take any contraceptive pill, and 1.6 times as likely to develop thromboembolism compared to women taking oral contraceptives containing levonorgestrel.

Pharmacology

Gestodene is a potent progestogen, and also possesses weak androgenic, antimineralocorticoid, and glucocorticoid activity. It has relatively high affinity for the androgen receptor (AR), with twice that of levonorgestrel (which is known to be one of the more highly androgenic 19-nortestosterone derivatives). However, the ratio of progestogenic to androgenic effects of gestodene is distinctly higher than that of levonorgestrel, and the increase in sex hormone-binding globulin (SHBG) levels (a marker of androgenicity) produced by oral contraceptives containing gestodene is slightly less than that produced by oral contraceptives containing desogestrel (which is known to be one of the more weakly androgenic 19-nortestosterone derivatives). In addition, no difference in acne incidence has been observed with oral contraceptives containing gestodene and oral contraceptives containing desogestrel. Moreover, gestodene has been found to strongly inhibit 5α-reductase in vitro (14.5% and 45.9% inhibition at 0.1 μM and 1 μM, respectively), and this action was substantially greater than that of desogestrel or levonorgestrel. Taken together, like desogestrel, gestodene appears to have a low potential for androgenic effects. In addition to the AR, gestodene has very high affinity for the mineralocorticoid receptor (MR), but only a relatively weak antimineralocorticoid effect that is comparable to that of progesterone. Gestodene binds to SHBG with relatively high affinity, and is 75% bound to the protein in circulation.

Although gestodene does not bind to the estrogen receptor itself, the drug may have some estrogenic activity, and this would appear to be mediated by its weakly estrogenic metabolites 3β,5α-tetrahydrogestodene and to a lesser extent 3α,5α-tetrahydrogestodene.

Based on the dosage necessary to inhibit ovulation in women, gestodene is the most potent of all of the currently used contraceptive progestogens. The oral dosage of gestodene required for ovulation inhibition is 30 or 40 μg per day. This is about 10,000 times lower than the oral dosage of progesterone required to inhibit ovulation (300 mg/day). A dosage of gestodene of 75 μg/day is used in contraceptives.

Chemistry

Gestodene is an estrane (C18) steroid and is also known as 17α-ethynyl-18-methyl-19-nor-δ¹⁵-testosterone or as 17α-ethynyl-18-methylestra-4,15-dien-17β-ol-3-one (as well as 13β-ethyl-18,19-dinor-17α-pregna-4,15-dien-20-yn-17β-ol-3-one). It is almost structurally identical with norgestrel (and levonorgestrel), differing only in having an additional double bond between the C15 and C16 positions. As such, it is also known as Δ¹⁵-norgestrel or as 15-dehydronorgestrel.

History

Gestodene was introduced in 1987.