The principal technique of hormonal methods of contraception, based on original studies by Pincus et al. (1958), has relied on the joint action of an oestrogen (mestranol) and a progestogen (norethynodrel) given cyclically for 20 days monthly. Combinations of other progestogens with either mestranol or ethinyloestradiol have also been studied. The biological and clinical basis of the antifertility effects of these agents were reviewed by Diczfalusy (1965) and by Rudel and Kincl (1966). The contraceptive mechanisms were described as (1) inhibition of ovulation, by both the oestrogen and the progestogen; and, fTom the anti-oestrogenic action of the progestogen, (2) a suppressed endometrium unfavourable to nidation, with (3) a cervical mucus hostile to spermatozoal motility. Definitive data on human tubal physiology relating to these agents have not been reported. Mestranol or ethinyloestradiol, given early and with regularity before ovulation, consistently inhibits its occurrence (Rudel and Martinez-Manautou, 1964; MartinezManautou and Rudel, 1966). Similar observations were made for ethinyloestradiol by Greenblatt et al. (1954). Thus, with the anti-ovulatory role of oestrogen and the anti-oestrogenic effects of progestogen defined, the concept of sequential therapy evolved-that is, early oestrogen for inhibition of ovulation, and later oestrogen plus progestogen to promote maturation of the endometrium with regular withdrawal bleeding. Oestrogen and progestogen, used concomitantly or sequentially, suppress the hypothalamic-pituitary-gonadal cycle, thus preventing ovulation and the normal endogenous regulation of the uterine bleeding cycle.On evaluating the contraceptive potential of the progestogen chlormadinone acetate in a daily dosage range of 0.5 mg. to 4 mg., a sensitivity differential was found between dosage and the development and degree of (1) inhibition of cervical mucus fluidity, (2) suppression of the endometrium, and (3) inhibition of ovulation (Rudel, 1964 ;Rudel et al., 1965Rudel et al., , 1967 MartinezManautou and Rudel, 1967). Within this range the highest doses produced all three effects, whereas on reducing the dosage to 0.5 mg. only inhibition of the cervical mucus was uniformly maintained; there was some endometrial suppression and, to a lesser degree, inhibition of ovulation. Though, originally, small numbers of women were studied, no pregnancies were seen with chlormadinone acetate 0.5 mg. daily. This suggested a method in which progestogen given uninterruptedly in small daily doses produces contraception without inhibiting ovulation, and if the pituitary-gonadal axis is not interrupted normal menstruation would occur.Prompted by these observations, Martinez-Manautou et al. (1966) carried out a clinical study to define the contraceptive effectiveness of a continuous daily dose of chlormadinone acetate 0.5 mg. Three hundred and twenty women were observed for 1,214 cycles, and two pregnancies were reportedone, as a failure of the method. Approximately 60% of the group had cycles ranging betw...
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