The progestogen-only pill

Chapter 6

The progestogen-only pill K. Fotherby

T h e Minipill - a limited alternative for certain women' was the title of a review of the progestogen-only pill (POP) in 1975 [1]. Unfortunately, the subsequent decade has seen little change in this viewpoint, although the POP with its many advantages deserves to be more widely used. Currently, its share of the oral contraceptive market is less than 7% in the UK, about 4% in Australia and less than 0.5% in the USA. In 1983, about 300 000 women in the UK were using a POP. This low usage largely reflects a reluctance on the part of the pharmaceutical companies to actively promote the POP. However, the advantages of the POP become more relevant as the limitations on the use of combined oestrogen-progestogen contraceptives increase, and the POP should be offered an equal place with other contraceptive methods. Two comprehensive reviews of the POP have been published [1,2] and these are supplemented by two further articles [3, 4]. Four progestogens (Figure 6.1) are formulated as POPs. All are 19-nor-steroids and two, lynoestrenol and ethynodiol diacetate, are rapidly converted in vivo in humans to norethisterone.

Figure 6.1 Progestogens formulated as progestogen-only pills. 94

Efficacy

95

Efficacy Cumulative results from a number of multicentre trials of the POP are shown in Table 6.1. Since 1976 when these values were tabulated, only three large-scale clinical trials have been reported. The values in Table 6.1 are still the most relevant ones because they involve large numbers of woman-years of treatment and give a realistic idea of failure rates. A failure rate of less than 3 per 100 woman-years of use would appear to be acceptable for a contraceptive method (Table 6.1), particularly if it has advantages over a method with a higher efficacy. Reduction of the daily dose below that shown in Table 6.1 usually leads to an increased pregnancy rate although, suprisingly, RuisVelasco et al [5] found that doses of ethynodiol diacetate of 250 to 500 |ig/day were equally effective. Increasing the daily dose usually leads to an increased incidence of irregular bleeding. The results of a few further clinical trials of the POP have been reported since the values in Table 6.1 were published in 1977. Postlethwaite [6] studied 309 women using ethynodiol diacetate for a total of 9566 cycles; six pregnancies occurred, two in women who missed tablets for 1 and 2 weeks. Based on the four tablet failures, the pregnancy rate (Pearl index) was 0.52 (confidence limits 0.14—1.33) per 100 womanyears. Lawson [7] reported the results of a multicentre trial involving 11 921 cycles of norethisterone 350 jig daily in 913 women. Of the 22 pregnancies which occurred, eight were in women who omitted to take the formulation and the remaining 14 in women who reported that they took the tablets regularly. The overall and method failure rates (Pearl index) were 2.2 and 1.4 per 100 woman-years respectively. In a randomized double-blind trial carried out in two centres in Yugoslavia and India [8], two POPs (norethisterone 350 fig and levonorgestrel 30 jag) were compared with two combined oral contraceptives (COC) containing the same progestogens (150ug levonorgestrel + 30 ug ethinyloestradiol and 1 mg norethisterone + 50 jig mestranol) in 518 women over 6092 cycles. Of the 34 pregnancies, 28 occurred in the Indian centre and 22 of these resulted from poor compliance with the instructions, whereas only one of the six pregnancies in Yugoslavia resulted from poor compliance. Twenty-two pregnancies occurred in women taking the POP, and the cumulative net life-table pregnancy rates after two years of use of the POP (9.5 for levonorgestrel and 19.6 for norethisterone) were not significantly different from those of the corresponding combined oral contraceptive. From the data supplied it is not possible to compute the Pearl index without making certain assumptions, but approximate values would be less than 2 per 100 woman-years for levonorgestrel and less than 4 for norethisterone. Table 6.1 Cumulative results of multicentre trials of progestogens administered daily (from [21)

Progestogen

Dose (fig daily)

Tradename

No. of woman-months of treatment No. of women

Pregnancy rate (Pearl index)

Ethynodiol diacetate Lynoestrenol Norethisterone

500

Femulen

24 534

2 420

2.1

500 350

37 405 26 173

4 731 2 925

0.9 2.3

dl-Norgestrel Levonorgestrel

75 30

Exluton Micronor, Noriday Neogest Microval, Norgeston

20 006 36 118

2 202 3 318

2.4 3.0

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Vessey et al. [9] obtained an overall failure rate of 0.9 pregnancies per 100 womanyears during a total period of use of 3303 woman-years; about one-half of the 30 pregnancies which occurred might have been due to incorrect pill taking. Most of the women were using norethisterone 350 ug daily. In a recent trial of Femulen [10] involving 425 women, the overall pregnancy rate was 1.6 per 100 woman-years (0.6 method failure, 1.0 patient failure); the total number of woman-years of use was not stated. Although for most of the trials the efficacy appears to be satisfactory, in some trials unacceptably high pregnancy rates have been reported. The cause of this variation is not apparent, but may reflect inadequate counselling of the subjects and noncompliance with the strict regime of tablet taking. As discussed below, it may be necessary with the POP to ingest it regularly at the same time each day, to relate administration to the pattern of sexual behaviour of the subjects, and to ensure that no tablets are missed. Also, the large variations between subjects in their metabolism of the POP and in their sensitivity at the target-organ level may imply that the dose, which is critical, whilst suitable for most women, may be inadequate for a few. The pregnancy rate with the POP appears to decrease with age [11]. In women aged 25-29 years the pregnancy rate was reported to be 3.8 per 100 woman-years falling to 2.9 in women aged 30-34 years and to only 0.8 in women over 35 years of age. This finding has been confirmed in a more recent analysis of the Oxford/FPA study [9]. Failure rates decreased from 3.1 pregnancies per 100 woman-years in women aged 25-29 to only 0.3 in those over 40 years of age. There is still controversy regarding the incidence of ectopic pregnancies in women using POPs. Bonnar [12] and Hawkins [13], and more recently WHO [8], found an incidence of 1-2 ectopic pregnancies per 100 woman-years of use, whereas Lawson [7] reported an incidence of only 0.3 per 100 woman-years. In the Oxford/FPA study [9], only one of 23 pregnancies which were not terminated was ectopic in 3303 womanyears of use. Bergsjo et al. [14] encountered nine tubal pregnancies in Norwegian women using 300 jig norethisterone daily, and although they could not relate these to the total use of this steroid, they considered that this figure represented an increased incidence, a conclusion also arrived at by Liukko et al. [15] for Finnish women. The latter authors further suggested that whereas the risk was about one ectopic pregnancy per 250-300 woman-years of use with 300 u.g norethisterone or 30 jig levonorgestrel, it was very much lower (1 per 1170 woman-years) for 500 |ig lynoestrenol; this finding is surprising in view of the known conversion of lynoestrenol to norethisterone in vivo and, if true, must result from the higher dose of lynoestrenol compared to norethisterone. These findings have been interpreted to suggest that the POP might be less effective in preventing ectopic pregnancies than intrauterine ones or, by inhibiting the mobility of the Fallopian tubes, might delay ovum transport and provide an increased opportunity for extrauterine implantation. However, the overall incidence of ectopic pregnancies appears to have increased in most countries during the past two decades [16, 17] and this has to be taken into account in assessing the incidence of ectopic pregnancies in POP users. From the clinical point of view women using POPs who present with symptoms of abdominal pain occurring after a light, delayed or missed period should be adequately investigated to exclude an ectopic pregnancy, and the possibility of pregnancy should not be dismissed just because she is using a steroidal contraceptive. A previous ectopic pregnancy is not an absolute contraindication to the POP, but clearly a combined oral contraceptive is preferred to protect the remaining Fallopian tube.

Clinical side-effects

97

Clinical side-effects Non-menstrual side-effects Non-menstrual side-effects appear to be minor and are usually considered to be less than those observed with combined oral contraceptives. Many women who have discontinued combined oral contraceptives because of side-effects appear not to have experienced them on using the POP. However, comparative trials of the POP and combined oral contraceptives show little difference in the incidence of non-menstrual side-effects [8, 18, 19]. In the WHO study there was little difference between the four preparations tested (norethisterone 1 mg + mestranol 50 u£, levonorgestrel 150ug + ethinyloestradiol 30 (ig, norethisterone 350 ug, and levonorgestrel 30 jig), except that discontinuations were highest for gastrointestinal symptoms (nausea, vomiting) with the levonorgestrel-oestrogen formulation and lowest with this formulation for central nervous system symptoms (headache, dizziness). In assessing the significance of the incidence of side-effects in contraceptive trials, the findings of trials such as those performed by Aznar-Ramos et al. [20] and Goldzieher et al. [21, 22], which showed no significant difference between women taking an oral contraceptive and those taking a placebo, are important. The POP does not appear to affect either the systolic or diastolic blood pressure. This was apparent from the early short-term (6 months) longitudinal study of Spellacy and Birk [23], using either norgestrel or ethynodiol diacetate. No changes were found in prospective studies over 2 years in women using norethisterone (350 jig) or norgestrel (75 ug) daily [7, 24]. An increased frequency of functional ovarian cysts often associated with pain has been demonstrated by ultrasound in women using a POP [25]. These cysts seem to disappear on discontinuation of the POP. Menstrual side-effects Disturbance of the menstrual pattern is regarded as the major disadvantage of the POP, and irregular bleeding, usually with an increase in the frequency, is the main cause of women discontinuing use. These changes in menstrual bleeding have been examined in detail [1, 2]. In women using the POP, the proportion of cycles of 25-35 days in length is about 55-65% compared to more than 80% in untreated women, whereas the proportion of cycles of less than 24 days is increased up to 30% compared to less than 5% in untreated women. Comparative trials also show the difference between POPs and combined oral contraceptives; Vessey et al. [18] found the proportion of cycles of length 25-31 days in women using POPs to be about 30% lower than in women using combined oral contraceptives. However, the high-dose oral contraceptives in use at that time would have magnified the difference between the two types of contraceptives. In the WHO Study [8], discontinuation for bleeding disturbances amongst women using POPs was similar to that of women using norethisterone 1 mg + mestranol 50 |ig, but significantly higher than that of women using levonorgestrel 150 ug + ethinyloestradiol 30 ug. There was no significant difference, however, between the two POPs in the incidence of irregular bleeding or discontinuations for menstrual disturbances. Another important aspect of the menstrual disturbances noted in trials is that as use of the POP continues, the percentage of short cycles shows a decrease. This partly reflects that women who experience a marked effect or find it inconvenient discontinue use of the POP, and is partly an actual decrease in the menstrual irregularity. In

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the trial of Postlethwaite [6], about 100 women completed 36 cycles of treatment and 22 completed 84 cycles, but only 15% of the women discontinued because of irregular bleeding. This suggests that, for the majority of the women, disturbance of the menstrual pattern was not marked enough to be considered important. An increased proportion of cycles of normal length and a decrease in short cycles with duration of treatment is evident from the data of Lawson [7]. Ferrari et al. [26] also suggested that the increasing proportion of cycles of normal length with continued treatment was not an artefact due to women with irregular cycles withdrawing, and in a group of women who had used norgestrel for 28-88 months [27] the frequency distribution of cycle lengths was similar to that of normal women. In respect of the duration and quality of the menstrual flow a summary of the findings [1] suggests that there are no major changes compared to pretreatment values. From the clinical point of view what is important is the group of women who show very prolonged cycles (greater than 45 days, up to 12% of women) or amenorrhoea (varying from 3% to 15% depending upon definition), since the possibility of pregnancy would arise. Now that simple, quick methods of pregnancy testing are available, this possibility is easily checked. Although there is no evidence to suggest that administration of low doses of progestogens as in the POP is associated with a teratogenic effect [28], it would of course be good practice not to continue the POP if the woman were pregnant. Oestrogen administration should not be used to attempt the control of irregular bleeding since this would negate one of the advantages of the POP and, more importantly, may counteract the chief contraceptive effect of the progestogen on the cervical mucus. Changes in the vasculature of the endometrium in women using a POP have recently been described [29], and may be related to the high incidence of irregular bleeding in these women. Return of fertility after discontinuation The POP does not produce a delay in the return of fertility after discontinuation, and prolonged post-pill amenorrhoea, occasionally reported after discontinuation of COCs, is seen less often. The occurrence of pregnancies in women using the POP or after missing pills shows that there is no long-lasting inhibition of fertility. This has been borne out by reports of the frequency of pregnancy amongst women who have discontinued the POP. Of six women in the trial of norgestrel by Eckstein et al. [30], who discontinued to become pregnant, all succeeded within 6 months. Similarly 13 of 14 women who stopped using norethisterone to become pregnant, did so within 6 months [31]. Sixteen women who had used lynoestrenol for at least 1 year and stopped in order to become pregnant conceived within 3 months [32]; all had normal pregnancies and all infants were healthy. In the Oxford/FPA study [9], 83 women discontinued the POP to become pregnant. Compared to women who had discontinued use of a diaphragm to become pregnant, rates in the POP group were less favourable but the differences were not statistically significant.

POP in lactating women Lactation is widely regarded as being a contraindication for use of COCs, since they may reduce lactation and there is the possibility (although evidence to support it is lacking) that the transfer of the steroid to the infant in milk may have adverse effects.

POP in lactating women

99

In contrast, the POP is eminently suitable for use in lactating women. Progestogens when administered alone appear not to reduce the volume of milk secreted nor the duration of lactation, and some reports suggest that they may increase both [1, 33]. The proportion of the POP administered to the mother which is transferred in the milk appears to be very small and is unlikely to present a hazard to the infant. Of eight women receiving norethisterone 300 jig daily [34], four had no detectable amounts of the steroid in the milk 3-5 h after pill administration, whilst in the remaining four the concentrations were below 350pg/ml; similar amounts were reported in another study [35], although a third study reported concentrations of 370-790 pg/ml 4 h after administration and 108-287 pg/ml at 24 h [36]. Because of the smaller dose of norgestrel used as a POP, the concentrations in milk are lower than those of norethisterone. In five women receiving 30 |ig levonorgestrel daily, Nilsson et al. [37] could not detect any of the steroid even at early times after administration but others [38] have reported concentrations of 38-135 pg/ml at unspecified times after administration. Using daily doses of levonorgestrel of 50 jig, the concentration at 2-3 h after administration was 50-200 pg/ml [35] and undetectable after 4 h. It seems, therefore, that the amount of the POP being transferred to the milk of lactating women is very small - too small to have any significant effect. As expected, the highest concentration of the progestogen in milk occurs in the first 4 h after administration of the POP; if we assume, e.g. for norethisterone, a concentration of 400 pg/ml milk and the infant ingests 100 ml milk, the amount it receives is 40 000 pg. Assuming a body weight of 5 kg, and an even distribution of the steroid, the concentration would be only 8 pg/ml. This calculation assumes that no metabolism of the steroid by the infant occurs, and this concentration would be below the limit of sensitivity of present methods of estimating the progestogen. This agrees with the findings [37, 39] that no progestogen was detected in the blood of suckling infants of women using progestogens. In a study involving 84 lactating women [40] using 350 |ig norethisterone daily, 44% were still using it 6 months postpartum and it appeared to have no adverse effect on breast-feeding. In this group of women, a high proportion (68%) of those breastfeeding for over 5 months were amenorrhoeic, so that the main problem with the POP - irregular bleeding - was not important. A number of studies have provided limited information that the POP does not affect the composition of the milk. Gupta et al. [41] studied 30 Indian women receiving 50 |ig norgestrel daily over a period of 4 | months after delivery and found no change in milk volume or the quality of the milk compared to a control group. In another study [42], using 30 \ig levonorgestrel daily, the drop-out rate was high but over a 3-month period there were no significant changes in milk volume or in the concentration of total nitrogen, non-protein nitrogen, a number of important proteins, and lactose. Betancourt et al. [43] compared 76 lactating women receiving 500 (ig lynoestrenol daily to similar numbers of women using an IUD or a barrier method of contraception; there were no significant differences between groups in the growth pattern of the infants as measured by body weight, length, and head circumference. The quality of milk produced was not decreased by the POP and the average duration of breast-feeding did not decrease over the 6 months of the study. There was no difference between the groups in the time of starting supplementary feeds. Unlike the COC, the POP does not affect lactation or the risk of venous thrombosis, and it is possible to start it in the immediate postpartum period. However, there is some evidence that an increase in the number of discontinuations

100

The progestogen-only pill

because of abnormal bleeding (increased lochia) may result (Unpublished observation). Hence, in the UK the Family Planning Association and similar bodies now recommend delaying commencement until about 4 weeks after childbirth.

Metabolic effects The POP produces few metabolic changes and those which do occur are minor ones. Carbohydrate metabolism The combined oral contraceptive affects the blood glucose and insulin responses to an oral glucose tolerance test, whereas a large number of early investigations showed that the POP produced little, if any, effect. These findings were confirmed [44] in a group of women using 500 jig ethynodiol diacetate daily, and this treatment also did not affect the levels of glycohaemoglobin (Hb Aj). However, in eight Cuban women treated with 350 jig norethisterone acetate daily for two months, significant deterioration of glucose tolerance occurred [45]. Spellacy et al. [46] published the results of a prospective study of 50 women studied before and after 18 months use of 75 \ig norgestrel daily; they found significant increases in the fasting glucose concentration and the glucose and insulin responses to an oral glucose tolerance test. In eight women the response to an oral glucose tolerance test was classified as abnormal. The effect of the POP in diabetic women was investigated by Radberg et al. [47, 48]. Twenty-three women with insulin-dependent diabetes were allocated randomly to a POP (lynoestrenol 500 (ig daily) or a combined oral contraceptive (lynoestrenol 2.5 mg, ethinyloestradiol 50 jig daily). After 6 months treatment, the subjects had two-months without medication and this was followed by 6-months use of the other formulation. During treatment with the COC, 13 of 23 women required an increased insulin dose and there was an increase in urinary glucose excretion, although the fasting blood sugar concentration did not change; similar changes were observed during treatment with the POP except that the insulin requirement was less. In a second study using a similar crossover design, women who had had diabetes during pregnancy were investigated using an intravenous glucose tolerance test. During treatment with the COC all women showed a lower glucose tolerance compared to only one in the POP group; no significant difference occurred in either the fasting blood glucose level or the insulin response. The authors conclude that lynoestrenol alone had little effect on glucose tolerance in women predisposed to diabetes. Steel and Duncan [49] reported on the use of 350 jig norethisterone daily in 50 insulindependent diabetic young women over a period of 1050 woman-months of use. No increase in insulin dosage appeared necessary and the women took the pill at the time of their insulin injection. Only one pregnancy occurred - in a woman who missed taking a number of pills. Disturbance of the menstrual pattern was not a problem. No significant changes occurred in the incidence or severity of retinopathy during the period of observation. Spellacy [50] reported that of the low-dose POP formulations, norethisterone produced only mild changes in blood glucose and insulin levels, ethynodiol diacetate produced moderate changes, and norgestrel marked ones. These conclusions, however, do not appear to be supported by a consensus of the results [51].

Metabolic effects

101

Lipid metabolism Early studies [2] showed that the POP had little effect on a number of aspects of lipid metabolism such as blood concentrations of cholesterol, triglycerides, free fatty acids and phospholipids. However, these studies were performed before the importance of the lipoproteins was recognized. Subsequent studies have confirmed the earlier findings and show no significant changes in high-density lipoprotein cholesterol [47, 52], although others [53] have suggested a small reduction in HDL 2 . Blood coagulation The extensive studies of Poller [54] showed that chlormadinone acetate 500 |ig daily did not affect a large number of haematological measurements, and numerous other studies [2, 55] have shown that the POP, unlike COCs, does not affect blood clotting and platelet aggregation. Ylikorkala et al. [56] measured the levels of two prostaglandins which have important effects on platelet-vascular interactions; prostacyclin (PGI2), produced in the vascular endothelium, causes vasodilatation and is a potent inhibitor of platelet aggregation, whereas thromboxane A2, produced in platelets, causes vasoconstriction and enhances platelet aggregation. They performed a crosssectional comparison of a group of women using various POPs (nine using levonorgestrel 30 |ig daily, nine lynoestrenol 500 jig daily, and six norethisterone 300 |ig daily; mean duration of use 3.7 ± 2.0 years), with a control group and a group using various COCs. Prostacyclin concentrations were decreased in women using COCs but not in the POP group. COCs did not affect thromboxane concentrations but these were depressed in the POP group, particularly in women using levonorgestrel. This is evidence against the likelihood of an increased risk of thrombosis during the use of POPs. Miscellaneous effects The POP appears to have little effect on liver function whether this is assessed by bromsulphthalein excretion or by measurement of blood enzyme activity, mainly transaminases [2, 45]. The hepatic synthesis and secretion of a large number of different proteins can be stimulated by administration of oestrogens; these proteins are involved in a large range of physiological functions, e.g. transport of hormones, vitamins, and minerals, control of aldosterone secretion, and immunological processes. The stimulatory effects of oestrogen can be suppressed to varying extents by concomitant administration of a progestogen, because of its antioestrogenic activity. The extent of the suppression depends on the nature and dose of the progestogen and on the particular protein measured. However, progestogens administered alone have little if any effect on the blood concentrations of these proteins [51, 57]. Ultrastructural changes in liver-cell morphology, detectable by electron microscopy but not by light microscopy, have been observed in liver biopsies from women using the POP [2] but the significance of these results is difficult to assess. The POP does not appear to affect thyroid or pituitary-adrenocortical function. Administration of various formulations did not affect protein-bound iodine or thyroxine concentrations, tri-iodothyronine uptake, or the free thyroxine index [2, 45]. Similarly, no changes have been detected in pituitary-adrenal function as assessed by plasma Cortisol levels, Cortisol secretion rate, response to ACTH or metyrapone stimulation, or dexamethasone suppression and the free Cortisol index [2].

102

The progestogen-only pill

Mechanism of action Effect on pituitary-ovarian function The original investigations of Martinez-Manautou et al. [58] with chlormadinone acetate suggested that ovulation was not always inhibited. More detailed studies [59] in women using 50 ug norgestrel daily showed on the basis of urinary hormone estimations (LH, oestrogens, and pregnanediol) that normal ovulatory cycles occurred in about 50% of the women. In the remainder, variable effects were noted; some showed a mid-cycle peak of LH excretion whereas in others it was absent. Pregnanediol excretion was low in most studies, suggesting a suppression of luteal activity, although less marked effects were observed on oestrogen production. This led to the suggestion that in some women there was déficient luteal function, possibly due to a suppression of LH secretion, and in others possibly due to a direct effect of the progestogen. The progestogen did not interfere with corpus luteum development, since in a study [60] of women undergoing laparotomy during treatment with norgestrel, a histologically normal corpus luteum was present in most instances. The effect of the progestogen seemed to be on corpus luteum function, since progesterone production, studied in vitro by these histologically normal corpora lutea, was reduced compared to synthesis of progesterone by corpora lutea from non-treated women [61]. The presence of corpora lutea histologically normal by both light and electron microscopy has been reported by a number of investigators (see [2]). The variable suppression of progesterone and LH production but with a lower effect on oestrogen production, based upon either urinary or blood estimations, has been well documented (see [2]). The main effect appears to be a direct one on the ovary, since the POP, in contrast with COCs, does not inhibit the ability of the pituitary to respond to LHRH [62]. A detailed study of hormonal changes in 43 women using 300 jig norethisterone daily, involving daily blood sampling, has been published [63-65]. A pattern of hormonal changes similar to that seen in a normal ovulation cycle was observed in 40% or ten subjects; 2 1 % had normal follicular activity with suppressed luteal function; 23% had normal or increased follicular activity with no luteal function; and 16% showed no signs of either follicular or luteal function. In these women, the variable suppression of the ovary was not related to the degree of inhibition of pituitary FSH and LH secretion. The pattern of the ovarian reaction to the POP may vary with duration of use; of a group of 21 women, eight who showed an ovulatory pattern of ovarian steroid secretion during the second cycle of use also showed a similar pattern during the sixth cycle. None of the remaining 13 women who showed absent or suppressed luteal function during the second cycle showed normal luteal activity during the sixth, although variability of their ovarian response compared to the second treatment cycle occurred. As hypothesized previously [2], the degree of suppression of progesterone synthesis will depend to a great extent on the intrinsic enzyme activity of any particular corpus luteum. In a recent study [25], only six of 21 POP users appeared to ovulate normally, and anovulation may be associated with cyst formation in the ovary. Ovulation inhibition by the POP may be increased by concomitant administration of the dopamine antagonist sulpiride [66]. Thus, there is a wide spectrum of response of the ovary to the POP, ranging from almost no effect on ovulation to various degrees of luteal and follicular suppression and anovulation in one direction, as opposed to stimulation of oestrogen secretion in the other. Such wide variability in ovarian steroid secretion may have a marked effect on the bleeding pattern.

Mechanism of action

103

Effect on tubal and uterine function The POP has a marked and variable effect on both the Fallopian tubes and the uterus. Progestogens will affect both tubal contractility and the rate of ovum transport and also affect tubal histology. They may also affect the fertilization process in the Fallopian tube and some suggest they also affect the capacitation of spermatozoa. However, as far as the human is concerned, these effects need to be confirmed with the progestogens currently used as POPs and in their present dose. There is more evidence for an effect of the POP on the endometrium, one obvious effect being the increased incidence of irregular bleeding. Many have reported changes in endometrial histology, particularly during the secretory phase. This is to be expected in view of the variable effects of the POP on ovarian steroid secretion and the administration of POP from day 1 of the cycle. A detailed study of endometrial morphology in women taking 300 |ig norethisterone daily has been reported [65]. An endometrial biopsy was taken and ovarian steroid secretion assessed during a pretreatment cycle and repeated during the second cycle of treatment. In this second cycle, biopsies were taken either between days 23 and 25 or, in those women who showed intermenstrual bleeding, within 6 hours of the onset of the bleeding. The only observable difference between biopsies from those women who had intermenstrual bleeding and those who did not was a larger glandular diameter in the latter; there was no correlation of the endometrial picture with normal or suppressed ovarian function. However, administration of norethisterone produced a number of significant changes in the endometrium: a reduced number of endometrial glands, decreased glandular diameter, a reduction in the amount of double-stranded polynucleotides and DNA per cell nucleus, and an increased number of plasmolemmal vesicles. The proliferative activity of the endometrium was suppressed. Only a minority of the subjects showed a normal secretory endometrium. The extent to which these changes would prevent implantation of the blastocyst is unclear, particularly since the normal endometrial requirements for implantation are not known.

Effect on cervical mucus and sperm penetration Initial investigations with the POP ascribed its anti-fertility action to an effect on cervical mucus, and numerous studies have shown the amount of mucus at mid-cycle to be markedly reduced and its viscosity greatly increased. These changes are accompanied by a reduced ability of spermatozoa to penetrate the mucus under both in vitro and in vivo conditions, although a few reports suggest that the block to the passage of spermatozoa in vivo is not only the mucus but also some other effect at the endocervical level [1, 2]. Occasionally, mucus samples from treated women do allow sperm penetration [30]. Changes in a number of biochemical constituents of mucus, e.g. proteins and enzyme activities, as well as biophysical changes, occur under the influence of the POP. The effect of the POP is time-dependent. It has been shown [67-69] that after administration of the POP, the penetrability of mucus by sperm decreases within 2 4 h and remains low for the next 16-20 h before it begins to increase again. These findings suggest that if one of the main sites for the anti-fertility effect of the POP is the cervical mucus, its efficiency will depend on the time at which sexual intercourse takes place in relation to the time of taking the pill. Women, therefore, should be

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The progestogen-only pill

advised to take the POP at the same time each day and to relate the time of taking to their pattern of sexual activity. The effects of the POP, like COCs are widespread. The actions considered above are ones which can be investigated by existing methodology, and it is highly likely that effects on other processes, e.g. fertilization, which cannot be adequately examined, also occur. These widespread actions of the POP no doubt account for its high efficacy, since this does not seem explainable on the basis of any single one of the effects discussed above.

Starting, changing, and stopping the POP Advice given to women using or about to use the POP was recently reconsidered by a joint committee representing the Medical Advisory Panel of the Family Planning Association and the National Association of Family Planning Doctors [70]. Women should start the POP preferably on the first day of the menstrual cycle and do not require to use additional contraceptive protection. The POP should be taken at the same time each day. The pills have their greatest effect on the cervical mucus from about 4-20 h after being taken, although other aspects of their contraceptive action, such as effects on ovarian activity, may not be so time-dependent and may indeed be as important in contraceptive efficacy as the action on sperm penetration of the cervical canal. Women should record any changes in menstruation. Menstrual bleeding may become irregular or may be absent altogether. If the period is overdue it is unlikely that the woman is pregnant, provided she has been taking the POP regularly and as advised. If menstruation does not occur, the POP should be continued and the doctor consulted so that the possibility of pregnancy can be excluded. If a pill is forgotten it should be taken as soon as remembered and the next pill taken at the correct time. If the pill was more than 3 h overdue, contraceptive action may be lost and normal pill-taking should continue but with the use of another method for the next 48 h. If the woman has severe diarrhoea or vomiting, the pill may be poorly absorbed and in addition to the POP, another contraceptive method should be used for the duration of the upset and for the following 48 h. During short-term use of an enzyme-inducing drug, another method is again advised, but should be continued for the likely duration of the enzyme-induction effect (1-4 weeks). Women changing from COC should start the POP on the day after the last combined pill and no extra contraceptive precautions are required. When changing from the POP to a COC, the new pill should be started on the first day of bleeding. If the woman has amenorrhoea the COC could be started any time after pregnancy has been excluded.

Summary Positive attributes of the POP 1. An acceptable efficacy. 2. A good general tolerance - it is suitable for women who complain of side-effects with other contraceptive methods, especially combined pills.

References

105

3. Avoidance of side-effects in which oestrogens are implicated. 4. Minimization of side-effects in which progestogens are implicated. 5. Body tissues exposed to lower concentrations of exogenous steroid, and hence less effect on metabolic processes. 6. No consistent inhibition of ovulation, and therefore ready return of fertility on discontinuation. 7. Particularly suitable for women over 45 years of age for whom combined oral contraceptives are contraindicated (over 35 if a cigarette smoker). 8. Particularly suitable for women with hypertension or diabetes, for breast-feeding women, and possibly for those with a risk or past history of thrombosis (in this case, keeping careful records and good counselling are essential, since the data sheets still call the latter a contraindication). 9. With adequate counselling, continuation rates are similar to those for COCs. 10. Start on day one of the menstrual cycle, with no extra contraceptive precautions required; daily administration without a break, obviating the necessity to remember when to start the next pack. 11. Can be started immediately postpartum or post-abortion. Negative attributes of the POP 1. An efficacy lower than COCs. 2. A high incidence of disturbance of menstruation which is unacceptable to some women. 3. No large-scale epidemiological data to give indication of risk of serious sideeffects such as thromboembolism, cerebrovascular disease or coronary heart disease. 4. If pregnancy occurs, there may possibly be an increased risk of an ectopic pregnancy. A past history of the latter is therefore a strong relative contraindication to the POP. 5. Regularity of pill taking is essential. Time of pill-taking in relation to time of sexual intercourse may be critical, and taking the POP before going to bed should be avoided for the 'p.m. lover'; it is better to take it at another regular time. 6. Occurrence of functional ovarian cysts, often associated with pain. On the basis of present evidence, the POP appears to be a contraceptive method which should be more widely available. Many women will discontinue in the first few months of use because of disturbances of the menstrual pattern, but those women who do continue may find the disturbance lessens. For those who do not experience such disturbances the method is highly acceptable; a number of reports describe groups of women who have used the POP over long periods with confidence and satisfaction. There appears to be no reason why such women should not continue using the POP until they reach the menopause. Diagnosis of the latter can be facilitated by measuring gonadotrophin levels on and off treatment, as well as by noting the presence of vasomotor symptoms. In our present state of knowledge, it is not possible to decide whether any one POP has advantages over the others. References 1. RiNEHART, w. The Minipill - A limited alternative for certain women. Population Reports A No. 3, A53-A67(1975)

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2. FOTHERBY, K. Low doses of gestogens as fertility regulating agents. In Advances in Fertility Regulation (ed. E. Diczfaulsy), Scriptor, Copenhagen, pp. 283-321 (1977) 3. FOTHERBY, K. The progestogen-only contraceptive pill. British Journal of Family Planning, 8, 7-10 (1982) 4. GRAHAM, s. and FRASER, i. s. The progestogen-only mini-pill. Contraception, 26, 373-385 (1982) 5. RUIZ-VELASCO, v., MARISCAL, j . D. o., SALGADO, H. j . et al. Ethynodiol diacetate as a contraceptive.

Fertility and Sterility, 25, 927-934 (1974) 6. POSTLETHWAITE, D. L. Pregnancy rate of a progestogen oral contraceptive. Practitioner, 222, 272-275 (1979) 7. LAWSON, p. j . Experience with norethisterone 0.35 mg daily as an oral contraceptive. British Journal of Family Planning, 8, 84-89 (1982) 8. WORLD HEALTH ORGANIZATION. A randomized double-blind study of two combined and two progestogen-only oral contraceptives. Contraception, 25, 243-252 (1982) 9. VESSEY, M. p., LAWLESS, M., YEATES, D. and MCPHERSON, K. Progestogen-only oral contraception. British Journal of Family Planning, 10, 117-121 (1985) 10. SHROFF, N. D., PEARCE, M. Y., STRATFORD, M. E. and WILKINSON, p. D. Clinical experience with ethynodiol diacetate. Contraception, 35, 121-134 (1987) 11. VESSEY, M., YEATES, D. and FLAVEL, R. Progestogen-only contraceptives In Current Fertility Control. John Wyeth, Slough, pp. 1 5 (1979) 12. BONNAR, j . Progestogen-only contraception and tubal pregnancies. Lancet, 1, 170 (1974) 13. HAWKINS, D. F. Progestogen-only contraception and tubal pregnancies. British Medical Journal, 1, 387 (1974) 14. BERGSJO, P., LANGENGEN, H. and AAS, J. Tubal pregnancies in women using progestogen-only contraception. Acta Obstetrícia et Gynecologia Scandinavica, 53, 377-378 (1974) 15. LiUKKO, p., ERKKOLA, R. and LAAKSO, L. Ectopic pregnancies during use of low-dose progestogens for oral contraception. Contraception, 16, 575-580 (1977) 16. MERiK, o. Ectopic pregnancy during 1961 78 in Uppsala County, Sweden: Impact of demographic factors on overall incidence. Acta Obstetrícia et Gynecologica Scandinavica, 60, 545-548 (1981) 17. ROBINSON, N. and BERAL, v. Risk of ectopic pregnancy. Lancet, 2, 1247-1248 (1979) 18. VESSEY, M. p., MEARS, E., ANDOLSEK, L. and OGRINE-OVEN, M. Randomised double-blind trial of four oral progestogen-only contraceptives. Lancet, 1, 915-922 (1972) 19. PAULSEN, M. L., VARADAY, A., BROWN, B. v. and KALMAN, s. M. A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid. Contraception, 9, 497-506 (1974) 20. AZNAR-RAMOS, R., GINER-VELAZQUEZ, J., LARA-RICALDE, R. and MARTINEZ-MANAUTOU, J. Incidence of

side effects with contraceptive placebo. American Journal of Obstetrics and Gynecology, 105, 1144-1149 (1969) 21. GOLDZIEHER, J. W., MOSES, L. E., AVERKIN, E. et al. A placebo controlled double-blind cross over investigation of the side effects attributed to oral contraceptives. Fertility and Sterility, 22, 609-623 (1971) 22. GOLDZIEHER, J. W., MOSES, L. E., AVERKIN, E. et al. Nervousness and depression attributed to oral contraceptives; a double-blind placebo controlled study. American Journal of Obstetrics and Gynecology, 111, 1013-1020(1971) 23. SPELLACY, w. N. and BIRK, s. A. The effects of mechanical and steroid contraceptive methods on blood pressure in hypertensive women. Fertility and Sterility, 25, 467^70 (1974) 24. WILSON, E. s. B., CRUIKSHANK, J., MCMASTER, M. and WEIR, R. J. A prospective controlled study of the

effect on blood pressure of contraceptive preparations. British Journal of Obstetrics and Gynaecology, 91,1254-1260(1984) 25. TAYOB, Y., ADAMS, J., JACOBS, H. s. and GUiLLEBAUD, J. Ultrasound demonstration of increased frequency of functional ovarian cysts in women using progestogen-only oral contraception. British Journal of Obstetrics and Gynaecology, 92, 1003-1009 (1985) 26. FERRARI, A., MEYRELLES, J. c , SARTORETTO, J. N. and SOARES FILHO, A. The menstrual cycle in women

treated with d-norgestrel in continuous administration. International Journal of Fertility, 18, 133 (1973) 27. FOSS, G. L. and FOTHERBY, K. Long term use of daily administration of low doses of norgestrel as an oral contraceptive. Journal of Biosocial Science, 7, 269-272 (1975)

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