Contraceptives, oral combination products

Several progestins are used in combination products. Norgestrel (Ovrette) is a mixture of active and inactive enantiomers levonorgestrel (Norplant) is the active enantiomer. Levonorgestrel and norethindrone are the most potent synthetic progestins in oral contraceptive preparations. 

A systematic review of published data on the occurrence of headache with the more modest combination products now used has shown little indication that they have a clinically important effect on headache in most women (142). Headache that occurs during early cycles of oral contraceptive use tends to improve or disappear with continued use. No clear evidence supports the common clinical practice of switching from one oral contraceptive to another in the hope of attaining a lower incidence of headache. However, manipulating the extent or duration of estrogen withdrawal during the cycle may provide benefit. 

PBS listing on medical grounds, economic factors including cost-effectiveness are taken into account, as required by the National Health Act, 1953. Fixed combination products are seldom considered suitable for inclusion in the PBS. Notable exceptions to this norm are oral contraceptives and combination hormone replacement therapies. Any new listing which has the potential to cost the PBS more than 10 million in the first full year of reimbursement must be approved by the Federal Cabinet. Otherwise, applications are approved by the Health Minister. 

Prolonged treatment of women for 3-4 years with combination products, particularly those containing mestranol, may lead to an acquired form of subclinical diabetes [207, 208] but there is no evidence at present that in the normal woman such diabetes does not regress on discontinuation of treatment. Equally, there is no reason to assume that in the preclinical diabetic the administration of oral contraceptives will slow down the natural progression of the disease. This fact must be borne in mind in considering the effect of oral contraceptive administration in such cases. 

There is little doubt that combination products often relieve some of the symptoms associated with premenstrual tension [295, 119]. At the same time, there is little doubt that depression is the most distressing side effect encountered on oral contraceptive medication [296] and may affect up to 20 per cent of women [297-299]. 

Rose [305] reported the excretion of grossly increased amounts of xanthurenic acid in the urine of women taking combination products. A similar increase in tryptophan metabolites occurs in pregnancy and has been interpreted as indicating pyridoxine deficiency [306]. Dewhurst [307] subsequently postulated a causal connection between dysfunction of trytophan metabolism and certain types of depression. Winston [308] developed the concept further by suggesting that depression from oral contraceptive medication be treated with pyridoxine. Price and Toseland [309] have proposed routine inclusion of pyridoxine in oral contraceptive preparations. Developments will be awaited with interest. 

Other metabolic effects ascribed to oral contraceptives include increases in serum iron, total iron binding capacity and serum copper, which are apparently due to the progestagenic components [345]. In addition, quantitative immunodiffusion studies show that both pregnancy and oral contraceptive combination products change the serum levels of certain proteins and in particular those synthesised by the liver [346]. 

A major application is postmenopausal estrogen replacement therapy. Synthetic estrogens also are used as a component of oral contraceptive combination products (see below). 

The two synthetic steroidal estrogens which have attained the greatest degree of therapeutic use are ethinyl estradiol [57-63-6] (EE) (5) and its 3-methyl ether, mestranol [72-33-3]((5). In contrast to the naturally occurring estrone derivatives, these acetylenic analogues are orally active and are the main estrogenic components of combination oral contraceptives (see Contraceptives) and certain estrogen replacement products. 

Pharmacology Oral contraceptives (OCs) include estrogen-progestin combinations and progestin-only products. 

Prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, because some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding while on oral contraceptives shortly after starting St. John s wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John s wort. 

Suggestive case histories raised at an early phase the notion of a possible correlation of oral contraceptives with endometrial cancer. Among cases of endometrial cancer there seemed to be an excess of users of oral contraceptives, particularly of the early high-dose estrogen type. With the virtual demise of these early products, the situation seems to have reversed a 1983 study from the Centers for Disease Control (CDC) in Atlanta showed that women who had used fixed combinations for oral contraception at some time in their lives had a relative risk of endometrial cancer of only 0.5 compared with never-users (112). The protective effect occurred only in women who had used oral contraception for at least 12 months, and lasted for at least 10 years after withdrawal. The WHO adopted the same view in 1988 in the light of multinational data (113). As in the case of hormonal replacement therapy, the protective effect seems to be due to the progestogen component. 

Cyproterone acetate in combination with ethinylestra-diol is indicated for the treatment of women with severe acne and moderately severe hirsutism. This product has been associated with a greater risk of venous thromboembolism than oral contraceptives. However, in a rigorous case-control study the risk of venous thromboembolism with cyproterone acetate + ethinylestradiol was not significantly greater than the risk in women who took conventional oral contraceptives (25). 

Quantification of coagulation factors is notoriously difficult, because of the interrelations among the various components of the coagulation cascade, the broad range of normal values, and considerable inter-laboratory variability (52). This variability is illustrated by a WHO study of users of combined oral contraceptives, conducted on several continents, which showed statistically significant differences among clinical centers in prothrombin time, fibrin plate lysis, plasminogen, and activated partial thromboplastin time (SEDA-16, 464). Effects also vary between different populations, users of different doses, users of different products, and tests performed at different periods of the medication cycle (63,69). 

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