Gestodene

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Abstract
The newer progestogens gestodene, desogestrel and norgestimate were developed in an attempt to produce agents with more selective progestational activity that would improve cycle control and minimise metabolic changes and adverse events while effectively preventing pregnancy. In clinical practice, gestodene is combined with ethinylestradiol in monophasic or triphasic combined oral contraceptive preparations. The drug has pharmacokinetic advantages over the other new progestogens in that it is active per se (the others are prodrugs) and has high bioavailability (approximately 100%). The ability of gestodene-containing oral contraceptives to inhibit ovulation is similar to that of preparations containing other progestogens although the required dosage is lower. In common with oral contraceptives containing desogestrel or norgestimate, and in contrast with those containing levonorgestrel, gestodene-containing preparations are associated with neutral or positive changes in lipid and carbohydrate metabolism. The effects of gestodene preparations on coagulation parameters, like those of desogestrel and levonorgestrel, are balanced by changes in the fibrinolytic system. Although the impact of these changes on clinical cardiovascular end-points has not been determined, the altered lipid profile is not likely to have significant clinical relevance because of the predominantly thrombogenic nature of cardiovascular disease in oral contraceptive users. Pregnancy rates and Pearl Indices with gestodene-containing preparations are low and similar to those with preparations containing other progestogens. Most pregnancies are attributable to user failure. Cycle control appears to be better with gestodene preparations than with levonorgestrel preparations, and available data suggest that cycle control may also be better with monophasic gestodene/ethinylestradiol than with monophasic desogestrel- or norgestimate-containing preparations, and better with triphasic gestodene- than with triphasic levonorgestrel- or norgestimate-containing preparations. However, differences between the new progestogen-containing preparations need to be confirmed in further large-scale trials. The most common adverse events with gestodene/ethinylestradiol are headaches and breast tension; the incidence of short term adverse events, including acne, is similar to that with preparations containing other progestogens. Changes in blood pressure and bodyweight are negligible. There are no comparative data on the incidence of cardiovascular events with gestodene-containing and other combined preparations. While the risk of breast cancer appears to be increased with long term combined oral contraceptive use in certain patient subgroups, this risk needs to be balanced against the noncontraceptive benefits of these preparations. Thus, there is evidence to suggest that gestodene-containing oral contraceptives may have advantages over those containing desogestrel or norgestimate in terms of cycle control, and also over more established progestogen-containing preparations in terms of cycle control, lipid metabolism and possibly carbohydrate metabolism. However, the impact of the observed metabolic changes on cardiovascular end-points are unknown and further large clinical trials are required to confirm the possible advantages of gestodene in terms of cycle control over the other new progestogens. The ability of gestodene-containing oral contraceptive preparations to inhibit ovulation is similar to that of preparations containing the other new progestogens desogestrel and norgestimate as well as more established progestogens. The dosage of gestodene required to inhibit ovulation is lower than that for other progestogens, and preparations containing gestodene may have a greater suppressive effect on the hypothalamic-pituitary axis. Furthermore, the dosage of progestogen required to transform the endometrium appears to be lower for gestodene and desogestrel than for norgestimate and levonorgestrel. Gestodene binds to the human progesterone receptor with a lesser affinity than that of 3-keto desogestrel and levonorgestrel. Gestodene also binds to the rat androgen receptor, with a similar affinity to that of 3-keto desogestrel and levonorgestrel. The antiestrogenic activity of gestodene [in terms of changes in sex hormone-binding globulin (SHBG) levels] is less than that of levonorgestrel and similar to that of desogestrel; the relative binding affinity of gestodene for SHBG is slightly greater than that of levonorgestrel and 3-keto desogestrel. However, no significant differences in effects on testosterone levels have been reported in women receiving contraceptive preparations containing one of these progestogens. The binding affinity of gestodene for animal mineralocorticoid and, to a lesser extent, glucocorticoid receptors appears to be greater than that of levonorgestrel or desogestrel. Although several differences between the pharmacodynamic effects of gestodene and norgestimate have been reported, they are likely to be of little clinical relevance because norgestimate is rapidly metabolised in vivo and levonorgestrel accounts for at least part of its activity. In common with desogestrel- and norgestimate-containing oral contraceptive preparations and in contrast with longer established high-dose combined oral contraceptive preparations, gestodene-containing formulations appear to have a neutral or favourable effect on the lipid profile although increased triglyceride levels have been reported. Oral contraceptives containing desogestrel tend to have a more favourable effect on high density lipoprotein-cholesterol levels than those containing gestodene. Although the effects of these lipid changes in terms of cardiovascular end-points have not been determined, their clinical relevance is likely to be low considering the thrombogenic nature of cardiovascular disease in oral contraceptive users. The overall effects of gestodene-containing preparations on haemostatic parameters appear to be similar to those of both desogestrel-and levonorgestrel-containing preparations, with small increases in some parameters associated with coagulation being balanced by an increase in fibrinolytic activity. Gestodene-containing combined oral contraceptive preparations administered for up to 1 year appear to have no or minimal effects on carbohydrate metabolism in healthy women and in women with diabetes mellitus. In common with desogestrel- and norgestimate-containing preparations, oral contraceptives containing gestodene appear to have fewer effects on carbohydrate metabolism than those containing longer established agents. Long term studies, especially in women aged >35 years, are needed to confirm the results of these short term studies. Gestodene is an active progestogen whereas the other 2 new progestogens desogestrel and norgestimate are prodrugs. As with other progestogens, the pharmacokinetics of gestodene show considerable intra- and interindividual variation. Gestodene has high oral bioavailability (almost 100%) and exhibits dose-linear pharmacokinetics. Maximum serum gestodene concentrations following multiple dose gestodene/ethinylestradiol administration are 4-fold higher than after single doses, and progressively increased during each and subsequent treatment cycles for up to 12 cycles. Area under the concentration-time curve (AUCo-24h) values for gestodene are approximately 5- to 8-fold higher after multiple gestodene/ ethinylestradiol administration than after single doses. AUC values for ethinylestradiol were greater after multiple monophasic or triphasic gestodene/ethinylestradiol administration than after single dose administration. Although gestodene strongly inactivates the cytochrome P450 CYP3A4, the major enzyme involved in the metabolism of ethinylestradiol, the drug does not appear to inhibit the metabolism of ethinylestradiol in vivo. Most available studies report no significant differences in ethinylestradiol concentrations between gestodene- or desogestrel-containing preparations. Gestodene is extensively metabolised by the liver; several metabolites have been identified including dihydro-gestodene, 3,5 tetrahydro-gestodene and hydroxy-gestodene. The clearance of gestodene is decreased and the terminal elimination half-life is increased with multiple dose compared with single dose gestodene/ ethinylestradiol administration; clearance is dependent on the free-fraction of drug and is therefore sensitive to changes in SHBG levels. In noncomparative trials of monophasic gestodene/ethinylestradiol 75μg/30μg (gestodene 75/30) or triphasic gestodene 50/30, 70/40, 100/30, pregnancy rates and Pearl Indices of 0 to 0.11% and 0 to 0.22, respectively, were reported during 6 to 36 cycles of administration to > 100 000 women, despite up to 14% of women missing at least 1 tablet in total. User failure accounted for most pregnancies. The efficacy of monophasic or triphasic gestodene-containing oral contraceptive preparations in preventing pregnancy appears to be similar to that of monophasic and triphasic desogestrel- and norgestimate-containing preparations and preparations containing the more established progestogens levonorgestrel or norethisterone. Pregnancy rates of 0 to 0.001% and Pearl Indices of 0 to 1 were reported despite a number of pill-taking errors; most pregnancies were attributable to patient failure. Evidence suggests that the effects of monophasic gestodene/ethinylestradiol on cycle control may be more favourable than those of monophasic desogestrel-, norgestimate- and levonorgestrel-containing oral contraceptive preparations although further large-scale comparative trials are required to confirm these findings. Cycle control with triphasic gestodene/ethinylestradiol also appears to be at least equal to that with triphasic norethisterone/ethinylestradiol or levonorgestrel/ethinylestradiol. Bleeding irregularities decreased after the first few cycles of use and were more common in women with a history of irregular bleeding and in first-time oral contraceptive users. The most common adverse events with monophasic and triphasic gestodene/ ethinylestradiol preparations are headache (0.6 to 13.1%) and breast tension (0.5 to 12.4%); less common are nervousness (0 to 8.4%), nausea (0 to 6%), depression (0 to 3.9%) and dizziness (0 to 2.9%). Weight gain and increased blood pressure are generally negligible and acne occurs in 0.3 to 5.8% of women. The incidence of these effects after 3 or 4 cycles was similar to that at baseline. The overall short term adverse event profile of monophasic gestodene/ ethinylestradiol was similar to that of desogestrel/ethinylestradiol, norgestimate/ ethinylestradiol and levonorgestrel/ethinylestradiol. Of note, the incidence of acne was similar to that with levonorgestrel, and tended to decrease from baseline more with gestodene- than with desogestrel- or norgestimate-containing preparations. Adverse events including headache, breast tension, nausea, depression and breakthrough bleeding led to treatment withdrawal in 2 to 8% of patients. No significant between-preparation differences in effects on blood pressure or body weight have been reported. Based on the apparently balanced effects of gestodene-containing oral contraceptive preparations on haemostasis, a relatively low risk of thromboembolic events is expected with these preparations. However, in common with other combined oral contraceptive agents, it is recommended that these preparations should be avoided in patients with a history of thromboembolic disease. There appears to be an increased risk of breast cancer with long term (≥4 years) oral contraceptive use in certain subgroups, especially in women aged 1 tablet has been missed, only the most recently missed tablet should be taken. If >12 hours have elapsed after missing 1 tablet, if >1 tablet has been missed or if vomiting or diarrhoea occurs, additional methods of contraception (i.e. barrier methods and spermicides) must be used for the following 7 days while the next 7 active tablets are taken. Additional contraception is also advised in patients receiving concomitant barbiturate, phenylbutazone, phenytoin, rifampicin (rifampin), griseofulvin, or antibacterial therapy. As with other combined oral contraceptives, there are a number of contraindications to gestodene 75/30 including pregnancy, thrombotic disorders, sickle cell anaemia, disorders of lipid metabolism, liver disease, breast or endometrial cancer and abnormal vaginal bleeding of unknown cause. Onset of migraine or exacerbation of pre-existing migraine, unusually frequent or severe headaches, acute visual or hearing disturbance, significant increase in blood pressure, jaundice, exacerbation of conditions known to be capable of deteriorating during oral contraceptive use or pregnancy, or suspicion of thrombosis or infarction are grounds for immediate withdrawal.