Hormonal Steroid Contraceptives: A Further Review of Adverse Reactions

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The past 5-year period has served to confirm that hormonal steroid contraception carries a significant degree of morbidity and a small but by no means negligible mortality. Thromboem-bolism remains the major hazard and prospective as well as further retrospective studies corroborate the evidence previously available. Association with stroke and with myocardial infarction seems to have been established and where other risk factors for either exist, such as smoking, hyperlipidaemia or hypertension, it would seem wise for other contraceptive measures to be used. Individual examples of occlusive episodes in other vascular beds continue to be reported. The rate of occurrence of thrombotic complications in older women requires justification by strong social, personal or other special reasons.

The pathogenesis of the vascular lesions occurring in association with oral contraceptives may have been clarified. An enhanced coagulability seems likely but an associated impairment of fibrinolytic activity may contribute to produce clinically relevant thromboembolism. The oestrogenicity of an oral contraceptive seems to determine its propensity to induce thromboembolic disease and this may be substantially or even preponderantly contributed to by the progestagen component. Occlusive lesions involving intimal proliferation have been demonstrated in a wide variety of vascular beds and suggest that female reproductive steroids may promote an intrinsic vascular lesion.

Hypertension develops more frequently in women on oral contraceptives than in an otherwise comparable group who are not taking them, and although generally of a modest degree, may at times be of disastrous severity. Evidence has been forthcoming of increased activity of both adrenergic and angiotensin mechanisms, as also has increased cardiac output and blood volume.

An increase in triglycerides may at times reach massive proportions and be accompanied by pancreatitis. A predilection for development of hyperlipidaemia by patients with types IV or V lipoprotein patterns may contraindicate use of combined oral contraceptives in such women.

Impairment of glucose tolerance appears early amongst women on combination contraceptives and bears resemblances to ‘steroid diabetes’. The increase in total plasma cortisol is not accounted for entirely by the bound fraction; unbound cortisol also being elevated.

Hepatic dysfunction consequent upon impairment of metabolic conjugation processes by sex steroids may interfere with elimination of endogenous and exogenous substances requiring conjugation. An enhanced liability to gallstone formation has been observed in both prospective and retrospective studies.

What were hitherto excessively rare benign hepatic tumours, have now been described in quite substantial numbers. The pathological categorisation has been clarified but associated profuse vascularity carries a risk of rupture with exsanguinating haemorrhage. A small number of such tumours have shown malignant degeneration. The tumours may at times be multiple. A possible aetiological association with steroid induced hyperplasia of intracellular organelles is suggested.

The possibility that oral contraceptives may be associated with other types of neoplasia remains under close scrutiny. A positive association of sequential oral contraceptives and adenocarcinoma of the endometrium has been suggested. However, a negative association of oral contraceptives with breast cancer incidence seems to suggest some sort of protective effect. Vaginal carcinoma in girls whose mothers had been treated with non-steroidal oestrogens in pregnancy has constituted a disconcerting reminder of the remote sequelae which may follow hormonal manipulation.

Hormonal contraceptives may be responsible for induction of symptomatic hepatic porphyria or elicitation of symptoms of an underlying porphyria variegata or intermittent porphyria. A possible association with fetal malformation has come under scrutiny as a result of a consistent grouping of certain malformations in infants having had intrauterine exposure during the vulnerable period of embryogenesis.

In the light of the data now available it has become increasingly necessary for oral contraceptive therapy to be under regular and well informed medical supervision. Renunciation of immediate medical responsibility for the health of women for whom they are prescribed would be entirely irresponsible.

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