Oral contraceptives, third

Gestodene Gestodene (54), along with norgestimate and desogestrel, are the progestin components of the third-generation oral contraceptives (see Contraceptives). It may be crystallised from hexane/acetone (81) or ethyl acetate (82), and its crystal stmcture (83) and other spectral data have been reported (84). 

The Advisory Committee on NHS Drugs, when examining oral contraceptives as one of the classes involved in the second phase of the limited list exercise, formed a preliminary position that the more expensive third-generation oral contraceptives should be precluded from availability on NHS prescription on grounds of cost. The outcry from women s groups, family planning practitioners and the medical profession was such that these proposals were never implemented. 

The incidence of serious known toxicities associated with the use of these drugs is low—far lower than the risks associated with pregnancy. There are a number of reversible changes in intermediary metabolism. Minor adverse effects are frequent, but most are mild and many are transient. Continuing problems may respond to simple changes in pill formulation. Although it is not often necessary to discontinue medication for these reasons, as many as one third of all patients started on oral contraception discontinue use for reasons other than a desire to become pregnant. 

And in another study it was found that users of oral contraceptives with second-generation progestogens have 30% greater increased risk of thrombotic diseases, a 260% greater increased risk of thrombotic deaths, and a 220% greater increased risk of post-thrombotic disability than users of oral contraceptives with third-generation progestogens (20). 

There are now reasons to doubt whether the third-generation oral contraceptives are indeed safer than their predecessors in respect to thromboembolism and substantial grounds for believing that they present greater risks. 

The laboratory findings therefore suggest that a greater thrombosis-inducing effect of the third-generation oral contraceptives can be explained and even anticipated on the basis of known mechanisms. Not all the relevant methods were available in the early years, but that relating to factor VII most certainly was. It is unfortunate, to say the least, that such work was either not performed or not properly interpreted. 

All in all, had a combination of hematological methods and field studies been initiated sufficiently soon, the increased risk of thromboembolism with the third-generation oral contraceptives could have been detected some years earlier, sufficient for society to take decisions on the benefit-to-harm balance of these drugs before so much needless injury was incurred. 

The third-generation oral contraceptives a judicial assessment... 

A 5-year case-control study involving all Danish hospitals has once more quantified the thromboembolic risks associated with oral contraceptives as a whole the risk with third-generation products was some 30% higher than with second-generation products (RR = 1.3 Cl = 1.0, 1.8) (123). However, data on cerebral thrombosis from the same study showed that with third-generation products the mean risk was some 40% lower than with second-generation products (RR = 0.6 Cl = 0.4, 0.9) (124). 

As has become clear since that time, these effects do not run parallel for all oral contraceptives the third-generation products, which contain either desogestrel or ges-todene, have rather different effects, the significance of which is unclear. 

Lipid changes seen with the most widely used combined oral contraceptives comprise an increase in low density lipoprotein and reductions in high density lipoprotein and cholesterol. The third-generation products have these effects to a much smaller extent, leading to claims that they would be less likely to have long-term adverse cardiovascular effects related to atherosclerosis. However, such a claim reflects an all too readily adopted belief that the lipid changes produced by the more traditional combined oral contraceptives are in this respect capable of causing this type of (primarily arterial) cardiovascular disease. This is of itself far from certain. 

Jaundice as a result of oral contraceptive treatment has been repeatedly described. Whereas in the Swedish population figures between 1 100 and 1 4000 were published when the early high-dose formulations were still in use (213), the overall incidence was estimated in 1979 at about 1 10 000 (9), and the current incidence is certainly further reduced. When such hepatic symptoms occur, they usually do so within the first month of medication (214), and jaundice may be accompanied by anorexia, malaise, and pruritus. Very few cases arise after the third month of medication and those reported are regarded by some as unlikely to be due to oral contraceptives. Microscopic examination of the liver shows intrahepatic cholestasis. When medication is stopped, symptoms usually disappear rapidly and the reaction does not seem to leave any sequelae (215). Genetic components seem to be important for the development of the reaction women who have experienced jaundice or severe pruritus in late pregnancy seem to be especially susceptible to jaundice or gallbladder disease when using... 

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